A preparation method of voriconazole for injection

Abstract

The present invention relates to a preparation method of voriconazole for injection, which comprises subliming and drying a mixed solution formed by injection water, sulfobutyl-β-cyclodextrin sodium and voriconazole after pre-freezing, and then drying by analytical drying to obtain voriconazole for injection, wherein the temperature is first lowered to below 50°C in the sublimation step, and then raised to above 10°C within 3 to 8 hours, the vacuum degree of the sublimation step is 0 to 10 Pa, the analytical drying time is 1 to 3 hours, the temperature is 55 to 70°C, and the vacuum is maintained for 3 to 10 hours. The present invention adjusts the steps and parameters of sublimation drying and analytical drying to make the prepared medicine have better stability to cope with more stringent high-temperature storage and transportation environments, and has fewer impurities and a shorter analytical drying time.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparation preparation technology, in particular to a preparation method of voriconazole 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] A Chinese invention patent (CN 111700864A) discloses a method for preparing voriconazole for injection. The method involves cooling, pre-freezing, and annealing a sample solution containing voriconazole, subliming the solution to an endpoint, and then subjecting the solution to desorption and drying. The sublimation process is divided into a first stage and a second stage, wherein the temperature in the first stage is higher than that in the second stage, and the pressure in the first stage is lower than that in the second stage. Both the first and second stages are conducted under conditions of a vacuum of no more than 20 Pa and a temperature of no more than 15°C. By adopting a sublimation method of high temperature and low pressure in the early stage and low temperature and high pressure in the later stage, the heat and mass transfer process is improved, crystallization uniformity is promoted, intra-batch variability is avoided, and reconstitution time is reduced. However, the above process steps are relatively cumbersome, and the drug is susceptible to the effects of storage and transportation environments. In particular, consideration is not given to whether the stability of the drug is affected under special conditions such as storage and transportation at higher temperatures. Therefore, the above issues need to be addressed. Summary of the Invention

[0004] The present invention provides a method for preparing voriconazole for injection. By adjusting the steps and parameters of sublimation drying and desorption drying, the prepared drug has better stability to cope with more stringent high-temperature storage and transportation environments, and has fewer impurities and a shorter desorption drying time.

[0005] To achieve the above-mentioned object, the technical solution of the present invention is: a method for preparing voriconazole for injection, which comprises pre-freezing a mixed solution formed by water for injection, sodium sulfobutyl-β-cyclodextrin and voriconazole, subliming and drying, and then performing desorption drying to obtain voriconazole for injection, wherein in the sublimation step, the temperature is first cooled to below -50°C, and then heated to above 10°C within 3 to 8 hours, the vacuum degree of the sublimation step is 0 to 10 Pa, the desorption drying time is 1 to 3 hours, the temperature is 55 to 70°C, and the ultimate vacuum is maintained for 3 to 10 hours.

[0006] As a further improvement, in the sublimation step, the temperature is first lowered to -65 to -50°C, and then raised to 10 to 20°C within 4 to 7 hours. The vacuum degree of the sublimation step is 3 to 8 Pa.

[0007] As a further improvement, in the sublimation step, the temperature is first lowered to -60 to -53°C, and then raised to 15 to 18°C ​​within 5 to 6 hours. The vacuum degree of the sublimation step is 4 to 6 Pa.

[0008] As a further improvement, in the sublimation step, the temperature is first lowered to -55 to -53°C, and then raised to 15 to 17°C within 5 hours. The vacuum degree of the sublimation step is 5 to 6 Pa.

[0009] As a further improvement, the analytical drying time is 2.3 to 2.8 hours, the temperature is 58 to 65°C, and the ultimate vacuum is maintained for 4 to 9 hours.

[0010] As a further improvement, the analytical drying time is 2.4 to 2.6 hours, the temperature is 60 to 63°C, and the ultimate vacuum is maintained for 5 to 8 hours.

[0011] As a further improvement, in the pre-freezing step, the temperature is lowered to -10 to 0°C within 0.5 to 3 hours and maintained for 3 to 5 hours, and the temperature is lowered to -45 to -30°C within 4 hours and maintained for 3 to 5 hours.

[0012] As a further improvement, in the pre-freezing step, the temperature is lowered to -5 to 0°C within 1 to 2 hours and maintained for 4 to 5 hours, and then lowered to -45 to -40°C within 1 to 3 hours and maintained for 4 to 5 hours.

[0013] Voriconazole for injection is prepared by the preparation method according to any one of claims 1 to 8.

[0014] Voriconazole for injection is prepared by the preparation method according to any one of claims 1 to 8, and maintains the stability of related substances under high temperature conditions of 55°C±2°C.

[0015] The above technical solution of the present invention has the following beneficial effects: by adjusting the steps and parameters of sublimation drying and analytical drying, the present invention makes the prepared medicine have better stability to cope with more stringent high-temperature storage and transportation environments, and has fewer impurities and shorter analytical drying time. DETAILED DESCRIPTION

[0016] 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.

[0017] "Some embodiments"

[0018] Process Description

[0019] The production process of voriconazole for injection includes bottle washing, stopper washing, aluminum-plastic cap sterilization, material preparation, liquid preparation, sterile filtration, filling, freeze-drying, capping, visual inspection and other processes.

[0020] Prepare the liquid according to the ingredients and parameters in Table 1.

[0021] Table 1 Production batch prescription

[0022]

[0023]

[0024] When the raw material content exceeds 100%, feed as 100%. The feed calculation formula is:

[0025]

[0026] 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 each vial with 21.2ml, half-stopper, and freeze-dry using a freeze dryer according to the following process.

[0027] Freeze-drying process

[0028] The filled product is transferred to the freeze dryer via a laminar flow cart. The freeze drying process is as follows: pre-freezing → vacuuming → primary drying → secondary drying → pressure increase → nitrogen filling → plugging → nitrogen pressure equalization → end.

[0029] Freeze-drying process parameters

[0030] Pre-freezing: The products are put into the box at room temperature. After putting them into the box, the partition is first cooled to -6~-2℃ for 0.5~2h and kept warm for 3~5h. Then the partition is rapidly cooled to -55~-40℃ (within 4h) and kept warm for 3~5h.

[0031] Sublimation drying: When the temperature of the refrigeration condenser drops below -50°C, start the vacuum pump and set the ultimate vacuum. When the vacuum degree in the freeze-drying box reaches 0.10mbar, start heating the plate layer and set the alarm vacuum to 0.20mbar. Raise the plate layer temperature to above 10°C in 3 to 8 hours and keep it warm for 65 to 70 hours.

[0032] Desorption drying: Set the ultimate vacuum and continue to heat the plate layer to 55-70℃ in 1-3 hours, and keep it warm for 8-10 hours.

[0033] Pressure rise test: The vacuum in the front chamber shall not exceed 0.1-0.5 mbar within 120 seconds, and the drying stage is completed.

[0034] Stop the machine and fill the freeze drying box with nitrogen. When the pressure in the box reaches 30-40 kPa before freeze drying, press the plug, level the nitrogen pressure, and take the box out and crimp the lid.

[0035] Fill the sample and start freeze-drying within 4 to 8 hours.

[0036] The auxiliary material sulfobutyl-β-cyclodextrin sodium comes from Sichuan Meida Kanghuakang manufacturer, batch number:

[0037] YBT221001S

[0038] Example 1

[0039] Preparation steps: Weigh water for injection, prepare the solution at 40°C, add sodium sulfobutyl-β-cyclodextrin and stir evenly, then add voriconazole, stir until completely dissolved, and then cool to 15°C. Add water for injection to the total amount, mix evenly, and filter. Filter through a 0.22μm polyethersulfone filter membrane, then fill, semi-press stopper, and freeze-dry using a freeze dryer according to the following process:

[0040] Pre-freezing: put into the box at room temperature, cool the plate layer to -4℃ within 60 minutes, keep it for 240 minutes, then quickly cool the partition (within 4 hours) to -45℃, keep it for 240 minutes.

[0041] Sublimation drying: The temperature of the refrigeration condenser is reduced to -50℃, and the vacuum pump is turned on to make the vacuum degree in the freeze drying chamber reach 3Pa. The plate layer is started to be heated, and the ultimate vacuum is controlled. The plate layer temperature is raised to 10℃ in 4 hours and maintained for 60 hours.

[0042] Desorption drying: Continue to heat the plate layer to 55°C in 2.3 hours, maintain the ultimate vacuum in the box, and keep warm for 4 hours.

[0043] Determination of the endpoint of analytical drying: After the analytical drying is completed, a pressure rise test is performed. The pressure rise within 1 minute should not exceed 0.05mbar (in the batch production process, it is used as the basis for determining the endpoint of analytical drying).

[0044] Unpacking: After drying, fill the box with nitrogen to a pressure of 30kPa. After fully plugging the injection bottles, add sterile nitrogen into the freeze dryer to normal pressure, and unpack and cap.

[0045] Among them, maintaining vacuum refers to maintaining the ultimate vacuum, which means continuously pumping the vacuum.

[0046] Example 2

[0047] The steps are the same as those in Example 1, except that:

[0048] Liquid preparation steps: add sodium sulfobutyl-β-cyclodextrin at a temperature of 45°C and stir evenly, then add voriconazole, stir until completely dissolved and then cool to 25°C.

[0049] Sublimation drying: The temperature of the refrigeration condenser is reduced to -55℃, and the vacuum pump is turned on to make the vacuum degree in the freeze drying chamber reach 5Pa. The plate layer is started to be heated, and the ultimate vacuum is controlled. The plate layer temperature is raised to 15℃ in 5 hours and maintained for 65 hours.

[0050] Desorption drying: Continue to heat the plate layer to 60℃ in 2.5h, maintain the ultimate vacuum in the box, and keep warm for 5h.

[0051] Determination of the endpoint of analytical drying: After the analytical drying is completed, a pressure rise test is conducted, and the pressure rises by 0.1mbar within 2 minutes (in the mass production process, it is used as the basis for determining the endpoint of analytical drying). Box out: After the drying is completed, the box is filled with nitrogen to a pressure of 35kPa.

[0052] Example 3

[0053] The steps are the same as those in Example 1, except that:

[0054] Liquid preparation steps: the liquid preparation temperature is 50°C, add sulfobutyl-β-cyclodextrin sodium and stir evenly, then add voriconazole, stir until completely dissolved and then cool to 30°C.

[0055] Sublimation drying: The refrigeration condenser temperature is reduced to -60℃, and the vacuum pump is turned on to make the vacuum degree in the freeze drying chamber reach 8Pa. The plate layer is started to be heated, and the ultimate vacuum is controlled. The plate layer temperature is raised to 18℃ in 6 hours and maintained for 68 hours.

[0056] Desorption drying: Continue to heat the plate layer to 65°C in 2.8 hours, maintain the ultimate vacuum in the box, and keep warm for 6 hours.

[0057] Determination of the endpoint of analytical drying: After the analytical drying is completed, a pressure rise test is performed, and the pressure rises by 0.08mbar within 3 minutes (in the batch production process, it is used as the basis for determining the endpoint of analytical drying).

[0058] Out of the box: After drying, the box is filled with nitrogen to a pressure of 40kPa.

[0059] Comparative Example 1

[0060] The same preparation process as in Example 1 was used, except that

[0061] Sublimation drying: The temperature of the refrigeration condenser is reduced to -45℃, and the vacuum pump is turned on to make the vacuum degree in the freeze drying chamber reach 12Pa. The plate layer is started to be heated, and the ultimate vacuum is controlled. The plate layer temperature is raised to 8℃ in 2 hours and maintained for 60 hours.

[0062] Desorption drying: Continue to heat the plate layer to 50℃ in 3 hours, maintain the ultimate vacuum in the box, and keep warm for 3 hours.

[0063] Determination of the endpoint of analytical drying: After the analytical drying is completed, a pressure rise test is performed, and the pressure rises by 0.15 mbar within 1 minute.

[0064] Out of the box: After drying, the box is filled with nitrogen to a pressure of 20kPa.

[0065] Comparative Example 2

[0066] The same preparation process as in Example 1 was used, except that

[0067] Sublimation drying: The temperature of the refrigeration condenser is reduced to -15℃, and the vacuum pump is turned on to make the vacuum degree in the freeze drying chamber reach 18Pa. The plate layer is started to be heated, and the ultimate vacuum is controlled. The plate layer temperature is raised to 0℃ in 2 hours and maintained for 60 hours.

[0068] Desorption drying: Continue to heat the plate layer to 30℃ in 3 hours, maintain the ultimate vacuum in the box, and keep warm for 3 hours.

[0069] Experiment 1: Process step exploration experiment

[0070] Voriconazole for injection was prepared using the preparation process of Test Examples 1-10, wherein the steps and parameters are shown in Table 2. Parts not shown are considered to be the same as the steps and parameters of Example 1 or “Some Examples”;

[0071] Table 2-1 Comparison of experimental parameters for each step

[0072]

[0073] Inspection path of the above process steps:

[0074] On the basis of Example 1, the process parameters of the analytical drying were adjusted to obtain Example 1. The specific parameters are subject to the table, and the influence of the analytical drying process on the stability experiment-accelerated test, the related substance 0-day detection test and the stability experiment-high temperature stability experiment was examined; then, on the basis of Example 1, the process parameters of the analytical drying were further adjusted to obtain Examples 2-4, so as to determine the preferred process parameters in the analytical drying step in the relevant test results; based on the preferred parameters in the analytical drying step, the various parameters of the sublimation drying step were adjusted to obtain Examples 5-7 and Example 9. After conducting the above-mentioned related detection tests, the preferred process parameters in the sublimation drying step were determined in the test results; further, based on the optimal parameters in the sublimation drying step, the various parameters of the analytical drying step were continued to be adjusted to obtain Example 8, and the various parameters of the sublimation drying and analytical drying steps were simultaneously adjusted to obtain Example 10 and examined simultaneously.

[0075] Furthermore, the same sublimation drying and desorption drying process as in Example 4 was used, and only the parameters of the pre-freezing step were adjusted to prepare voriconazole for injection to obtain Examples 11-13. The same sublimation drying and desorption drying process as in Example 10 was used, and only the parameters of the pre-freezing step were adjusted to prepare voriconazole for injection to obtain Examples 14-16. The steps and their parameters are shown in Table 2-2. The parts not shown are considered to be the same as the steps and parameters of Example 1 or "Some Examples"; this is used to explore the effect of the pre-freezing step on the stability of the drug.

[0076] Table 2-2 Pre-freezing step test parameters

[0077]

[0078] The voriconazole for injection prepared according to the preparation method of Test Examples 1-16 was subjected to the finished product stability test - high temperature test in Test Example 2 for observation.

[0079] Test Example 2 Stability Test-High Temperature Test

[0080] The voriconazole for injection prepared according to the preparation method of Test Example 1-16 was subjected to a stability test - high temperature test, and a high temperature influencing factor test was conducted to examine the stability of the drug under high temperature (55°C ± 2°C) conditions for 30 days. The results of the influencing factor investigation are shown in Table 3;

[0081] Table 3: Test results of high temperature influencing factors

[0082]

[0083]

[0084] Conclusion: Through comparison, it was found that the voriconazole for injection prepared by the preparation methods of Test Examples 2-7 can all be stored at 55°C ± 2°C, and the indicators of the relevant substances still meet the requirements. This shows that the drug can withstand more stringent high-temperature storage and transportation environments, and has better stability, fewer impurities, and shorter desorption and drying time.

[0085] A comparison revealed that the total impurities in the related substance test results of Test Examples 1, 8, and 10 all exceeded the standard requirements. Although the total impurities in Test Example 9 did not exceed the standard limit in the high-temperature test, the impurity B in its related substances exceeded the prescribed range in this test. Therefore, the drug stability of Test Examples 1 and 8-10 was poor in the high-temperature test. Therefore, Test Examples 1 and 8-10 cannot be stored and transported under high-temperature conditions.

[0086] Further comparison revealed that although Test Examples 11-13 and Test Examples 14-16 used the same sublimation drying and desorption drying steps as Test Example 4 and Test Example 10, respectively, the results did not change significantly after only adjusting the pre-freezing step and parameters;

[0087] The above high temperature test results further demonstrate that the sublimation step and the analysis step can improve the technical effect of drug stability.

[0088] Test Example 3 Finished Product Stability Test-Accelerated Test

[0089] The voriconazole for injection prepared according to the preparation method of Test Examples 1-10 was subjected to a stability test-accelerated test, simulating the marketed packaging under conditions of a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 3 months. The accelerated 3-month test was completed, and the results are shown in Table 4.

[0090] Table 4: Accelerated test results of related substances

[0091]

[0092] Conclusion: After three months of accelerated testing, the voriconazole for injection prepared according to the preparation method of Test Examples 1-10 was found to meet the requirements in all indicators and to have stable and controllable quality.

[0093] However, during the process of exploring the process steps, it was found that after 3 months of accelerated testing, the impurity contents of Test Example 2-7 were well controlled in the stability experiment - related substance detection results, and impurity B and other individual impurities were not detected. It can be seen that the various indicators of Test Example 2-7 are more in line with the regulations and the quality is more stable and controllable.

[0094] A comparison revealed that not only did impurity B appear in the relevant substance test results of Test Examples 1 and 8-10, but the impurity B in Test Examples 8 and 9 was close to the upper limit of the specified range during the 3-month accelerated test. Therefore, the drug stability of Test Examples 1 and 8-10 was poor and easily affected by the external environment.

[0095] According to the above accelerated test results, the improved sublimation and analysis steps can improve drug stability.

[0096] Test Example 4: Finished Product Inspection Test

[0097] The finished voriconazole for injection was prepared according to the preparation processes of Examples 1-3 and Comparative Examples 1-2, respectively, wherein the amounts of raw materials used are shown in Table 5, and the content, related substances, properties, etc. of the finished products were tested, and the test results are shown in Table 5.

[0098] Table 5 Test results of finished products

[0099]

[0100]

[0101] Note:

[0102] Impurity A: 1-(2,4-difluorophenyl)-2-(1h-1,2,4-triazol-1-yl)ethanone;

[0103] Impurity B: voriconazole pyrimidine ring defluorination impurity;

[0104] Impurity C: 4-ethyl-5-fluoropyrimidine.

[0105] Conclusion: The test results of the finished products prepared according to the processes of Examples 1-3 all met the requirements, and the quality was stable and controllable. The final production process was stable and applicable. Among them, Example 2 further optimized the parameters in each step based on the process steps of Examples 1 and 3, for example, controlling the time, temperature and time of the desorption drying, so that Example 2 was superior to Examples 1 and 3 and other comparative examples in the final test results.

[0106] Although the voriconazole for injection prepared by the preparation process of Comparative Example 1-2 meets the quality standards during the initial various index tests, the various impurities in the tests of its related substances are significantly higher than those in Examples 1-3. Therefore, although the finished product prepared by the product meets the standards, the quality may be damaged due to slight influences of various influencing factors. Therefore, the stability reliability of the finished drug of Comparative Example 1-2 is low.

[0107] Test Example 5 Finished Product Stability - High Temperature Test

[0108] The voriconazole for injection prepared according to the preparation method of Example 1-3 and Comparative Example 1-2 was removed from the outer packaging and subjected to an influencing factor test. The stability of Example 1-3 and Comparative Example 1-2 under high temperature (55°C ± 2°C) conditions for 30 days was investigated. The results are shown in Table 6. Table 6 High temperature test results

[0109]

[0110] Conclusion: As shown in the test results, the changes in the relevant substances in Examples 1-3 after being placed under high temperature (55°C ± 2°C) for 30 days are still within the standard range, indicating that the voriconazole for injection prepared according to the preparation methods of Examples 1-3 are highly stable, suitable for mass production, and can cope with more stringent transportation and storage conditions.

[0111] However, the comparative examples 1-2 did not produce ideal results in this experiment, had poor stability, and were not suitable for mass production.

[0112] Test Example 6 Finished Product Stability-Accelerated Test

[0113] The voriconazole for injection prepared according to the preparation methods of Examples 1-3 and Comparative Examples 1-2 was tested for 6 months at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The results of the accelerated 6-month test are shown in Table 7.

[0114] Table 7 Accelerated test results

[0115]

[0116] Conclusion: As shown in the test results, the changes in the relevant substances in Examples 1-3 after 6 months of accelerated testing, which simulated the market packaging being placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 30 days, were still within the standard range. This shows that the voriconazole for injection prepared according to the preparation method of Examples 1-3 has high stability, is suitable for large-scale production, and can cope with more stringent transportation and storage conditions.

[0117] However, the effects of Comparative Examples 1-2 in this experiment were not ideal, indicating that they had poor stability and were not suitable for mass production.

[0118] Note: The test indicators and test methods for the stability of finished products are shown in Table 8.

[0119] Table 8: Stability study test indicators and test methods

[0120]

[0121]

[0122] 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 method for preparing voriconazole for injection, comprising pre-freezing a mixture of water for injection, sodium sulfobutyl-β-cyclodextrin, and voriconazole, subliming and drying the mixture, and then performing desorption drying to obtain voriconazole for injection, wherein: In the sublimation step, the temperature is first lowered to below -50°C, and then raised to above 10°C within 3 to 8 hours. The vacuum degree of the sublimation step is 0 to 10 Pa. In the analytical drying step, the analytical drying time is 1 to 3 hours, the temperature is 55 to 70°C, and the vacuum is maintained for 3 to 10 hours.

2. The method for preparing voriconazole for injection according to claim 1, wherein: In the sublimation step, the temperature is first lowered to -65 to -50°C, and then raised to 10 to 20°C within 4 to 7 hours. The vacuum degree of the sublimation step is 3 to 8 Pa.

3. The method for preparing voriconazole for injection according to claim 1, wherein: In the sublimation step, the temperature is first lowered to -60 to -53°C, and then raised to 15 to 18°C ​​within 5 to 6 hours. The vacuum degree of the sublimation step is 4 to 6 Pa.

4. The method for preparing voriconazole for injection according to claim 1, wherein: In the sublimation step, the temperature is first lowered to -55 to -53°C, and then raised to 15 to 17°C within 5 hours. The vacuum degree of the sublimation step is 5 to 6 Pa.

5. The method for preparing voriconazole for injection according to any one of claims 1 to 4, characterized in that: The analytical drying time is 2.3 to 2.8 hours, the temperature is 58 to 65°C, and the ultimate vacuum is maintained for 4 to 9 hours.

6. The method for preparing voriconazole for injection according to any one of claims 1 to 4, characterized in that: The analytical drying time is 2.4 to 2.6 hours, the temperature is 60 to 63°C, and the ultimate vacuum is maintained for 5 to 8 hours.

7. The method for preparing voriconazole for injection according to claim 1, wherein: In the pre-freezing step, the temperature is lowered to -10 to 0° C. within 0.5 to 3 hours and maintained for 3 to 5 hours, and then lowered to -45 to -30° C. within 4 hours and maintained for 3 to 5 hours.

8. The method for preparing voriconazole for injection according to claim 1, wherein: In the pre-freezing step, the temperature is lowered to -5 to 0°C within 1 to 2 hours and maintained for 4 to 5 hours, and then lowered to -45 to -40°C within 1 to 3 hours and maintained for 4 to 5 hours.

9. A voriconazole for injection, characterized in that: The method is prepared according to any one of claims 1 to 8.

10. A voriconazole for injection, characterized in that: The preparation method according to any one of claims 1 to 8 is adopted, and the stability of related substances is maintained under high temperature conditions of 55°C±2°C.

Images