Isavuconazole sulfate for injection and technological process thereof

Abstract

The invention discloses isavuconazole sulfate for injection. The isavuconazole sulfate comprises the following raw materials and auxiliary materials: isavuconazole sulfate, an excipient, a proper amount of a sulfuric acid solution (the pH value is adjusted to 1.3-1.5) and water for injection. And the excipient is mannitol, threonine and povidone. By adding mannitol, threonine and povidone and controlling the reasonable proportion of the components, the pH value of the environment where the medicine is located is adjusted, and rapid dissolution of isavuconazole sulfate is achieved. The excipient adopts three components for synergistic interaction, so that the stability of the isavuconazole sulfate for injection is improved, and the generation of impurities is reduced. The prepared isavuconazole sulfate for injection has good stability under the environments of long-term storage, strong light illumination, high temperature, high humidity and the like.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to isavuconazole sulfate for injection and a process flow thereof. Background Art

[0002] Isavuconazole sulfate for injection, the chemical name is 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium hydrogen sulfate. Isavuconazole sulfate for injection is an antifungal drug and a prodrug of the triazole antifungal drug isavuconazole. It blocks the synthesis of ergosterol, a key component of the fungal cell membrane, by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-α-demethylase, thereby weakening the structure and function of the fungal cell membrane.

[0003] As an important antifungal drug, isavuconazole sulfate for injection has made significant progress in its preparation process. The preparation of isavuconazole sulfate for injection adopts a lyophilization process, and its main process flow includes liquid preparation, filtration, filling and lyophilization to finally obtain the finished product. However, to further improve its bioavailability and stability, reduce production costs and maintain production consistency, continuous efforts in technology research and development and process improvement are still needed. This will help to increase the popularity and therapeutic effect of its clinical application and bring good news to more patients.

[0004] Therefore, it is necessary to develop an isavuconazole sulfate for injection and its process flow, which is of great significance to solve the two problems of solubility and stability while ensuring the product content. Summary of the invention

[0005] In view of this, the present invention proposes isavuconazole sulfate for injection and its process flow to solve the above problems.

[0006] The technical solution of the present invention is achieved in this way:

[0007] Disclosed isavuconazole sulfate for injection comprises the following raw materials and auxiliary materials by weight: 30-40 parts of isavuconazole sulfate, 6-10 parts of excipients, an appropriate amount of sulfuric acid solution (adjusted to pH 1.3-1.5), and 300-400 parts of water for injection; the excipients are mannitol, threonine and povidone.

[0008] Preferably, the mass ratio of mannitol, threonine and povidone in the excipient is (6-8):(1-2):(1-2).

[0009] Preferably, the sulfuric acid solution is an 8 wt % sulfuric acid solution.

[0010] A process for producing isavuconazole sulfate for injection comprises the following steps:

[0011] S1. Liquid preparation: After adding water for injection to the liquid preparation container to 50-70% of the total amount of the liquid preparation, control the water temperature at 2-8°C. When the temperature of the water for injection drops to 8°C or below, add the weighed mannitol, threonine and povidone into the liquid preparation container and stir until they are completely dissolved. When the temperature of the liquid drops to <5°C, add the weighed isavuconazole sulfate into the liquid preparation container and stir until it is completely dissolved. Subsequently, adjust the pH value of the solution to 1.3-1.5 with sulfuric acid solution and replenish the water for injection;

[0012] S2, filtration and filling: the drug solution is filtered through a microporous filter membrane and then divided into vials, which are semi-stoppered to obtain a freeze-dried drug solution;

[0013] S3. Freeze-drying: freeze-dry the drug solution to be freeze-dried and then compress it completely to obtain isavuconazole sulfate for injection.

[0014] Preferably, the microporous membrane filtration in step S2 is specifically as follows: the drug solution is initially filtered through a 0.45um filter element, and then sterilized through two 0.2um filter elements; the filter element is made of polyethersulfone.

[0015] Preferably, the freeze-drying of S3 specifically comprises the following steps:

[0016] (1) Pre-cooling of the partition: Before feeding the freeze dryer, set the temperature of the heat transfer oil to 0-2°C;

[0017] (2) Pre-freezing: Set the temperature of the heat transfer oil to -50 to -40°C, keep it warm for 2 to 3 hours, and after the pre-freezing is completed, open the refrigeration box. When the temperature of the box reaches below -50°C, start vacuuming.

[0018] (3) Sublimation drying: After the vacuum degree of the current chamber drops to ≤0.2 mbar and stabilizes, raise the temperature of the thermal oil to -5 to 5°C and maintain it for 15 to 20 hours;

[0019] (4) Desorption and drying: After the constant temperature is completed, the temperature of the heat transfer oil is raised to 30-40°C and maintained for 10-15 hours, and then the temperature of the heat transfer oil is lowered to 10-20°C. After the ultimate vacuum is drawn for 20-30 minutes, a pressure rise test is performed to determine the freeze-drying endpoint;

[0020] (5) Nitrogen filling protection and full pressure plugging: When filling with nitrogen, observe that the vacuum value of the front box rises to -0.03MPa~-0.02MPa, stop the nitrogen input, let it stand for 3~5 minutes, and then perform the full pressure plugging operation on the product.

[0021] Preferably, the heating rate of the heat transfer oil in the sublimation drying and analytical drying is 0.3°C / min to 0.5°C / min; the cooling rate of the heat transfer oil in the analytical drying is 0.3°C / min to 0.5°C / min.

[0022] Preferably, the pressure rise test for judging the endpoint of freeze-drying is to close the septum valve, observe the change in the vacuum of the front box, and the vacuum is ≤0.02 mbar within 1 minute. After an interval of 5 minutes, repeat this operation twice. After three consecutive tests, freeze-drying is terminated. If the requirements are not met, continue to evacuate the vacuum to the limit until it is finally judged to meet the requirement of "≤0.02 mbar within 1 minute".

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention provides an isavuconazole sulfate for injection. By adding mannitol, threonine and polyvidone and controlling the reasonable ratio of several components, the pH value of the environment in which the drug is located is adjusted to achieve rapid dissolution of isavuconazole sulfate. Mannitol has good solubility, and threonine has a polar side chain, which helps to increase the solubility of isavuconazole sulfate in the aqueous phase and reduce drug precipitation and crystallization. In addition, the antioxidant properties of threonine can help prevent the drug from oxidative degradation during storage and use, thereby improving the stability of the drug; polyvidone can reduce adverse interactions between drugs, avoid the generation of impurities, improve the stability of the drug and reduce the generation of impurities; the three components synergistically enhance the stability of isavuconazole sulfate for injection. The isavuconazole sulfate for injection prepared by the present invention has good stability under long-term storage, strong light illumination, high temperature and high humidity and other environments. DETAILED DESCRIPTION

[0025] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0026] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0027] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0028] Example 1

[0029] Disclosed isavuconazole sulfate for injection comprises the following raw materials and auxiliary materials, measured by weight: 30 parts of isavuconazole sulfate, 6 parts of excipients, an appropriate amount of 8wt% sulfuric acid solution (adjusting the pH to 1.3-1.5), and 300 parts of water for injection; the excipients are mannitol, threonine and povidone, wherein the mass ratio of mannitol, threonine and povidone is 6:2:2.

[0030] The preparation method of isavuconazole sulfate for injection comprises the following steps:

[0031] S1. Liquid preparation

[0032] After adding water for injection to the liquid preparation bag to about 70% of the total amount of the liquid preparation, start cooling, start the tank stirring, set the stirring speed to 200rpm, and control the water temperature to 2-8°C; when the temperature of the water for injection in the liquid preparation bag drops to 8°C or below, open the feeding port and put the weighed mannitol, threonine and povidone into the liquid preparation bag, and stir until they are completely dissolved; when the temperature of the drug solution drops to <5°C, put the weighed isavuconazole sulfate into the liquid preparation bag, rinse the weighing container with 4% of the total amount of the liquid preparation water, merge the rinse liquid into the liquid preparation bag, and then stir for 35 minutes or more until it is completely dissolved; measure the pH of the intermediate drug solution, when it is greater than 1.5, adjust the solution pH to 1.3-1.5 with 8wt% sulfuric acid solution, continue stirring for about 5 minutes, take the solution to measure the pH value, add water for injection (water temperature 10-25°C) to the full amount (control the drug solution temperature below 8°C), and continue stirring for 15 minutes;

[0033] S2, Filtration and Filling

[0034] The drug solution was initially filtered through a 0.45um filter element [size: 5 inches, material: polyethersulfone (PES), brand: Cobetter], and then sterilized and filtered through two 0.2um filter elements [size: 5 inches, material: polyethersulfone (PES), brand: Cobetter]. The filtrate was filled into a vial and half-stoppered.

[0035] S3. Freeze-drying

[0036] (1) Pre-cooling of the partition: before feeding the freeze dryer, the temperature of the heat transfer oil is set to 0°C;

[0037] (2) Prefreezing: Set the temperature of the heat transfer oil to -40°C and maintain it for 2 hours. After the prefreezing is completed, open the refrigeration box. When the temperature of the box reaches below -50°C, start vacuuming.

[0038] (3) Sublimation drying: After the vacuum degree of the current chamber drops to ≤0.2 mbar and stabilizes, the temperature of the thermal oil is raised to 5°C at a heating rate of 0.3°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.2 mbar) and maintained for 15 hours;

[0039] (4) Analytical drying: After the constant temperature is completed, the temperature of the heat transfer oil is increased to 40°C at a heating rate of 0.3°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.05mbar), and maintained for 15 hours. The temperature of the heat transfer oil is reduced to 20°C at a cooling rate of 0.5°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.05mbar). After 0.5 hours, the aeration valve is closed, and the pressure rise test is performed after 20 minutes of extreme vacuuming. The middle diaphragm valve is closed, and the vacuum change of the front box is observed. It is ≤0.02mbar within 1 minute. Repeat this operation 2 more times after an interval of 5 minutes. If the test is qualified for 3 consecutive times, the freeze-drying is terminated; if it does not meet the requirements, the extreme vacuuming is continued until it is finally judged to meet the "≤0.02mbar within 1 minute";

[0040] (5) Nitrogen filling protection and full pressure plugging: When filling with nitrogen, observe that the vacuum value of the front box rises to -0.03MPa~-0.02MPa, stop the nitrogen input, let it stand for about 5 minutes, and then perform the full pressure plugging operation on the product.

[0041] Example 2

[0042] Disclosed isavuconazole sulfate for injection comprises the following raw materials and auxiliary materials, measured by weight: 35 parts of isavuconazole sulfate, 8 parts of excipients, an appropriate amount of 8wt% sulfuric acid solution (adjusting the pH to 1.3-1.5), and 350 parts of water for injection; the excipients are mannitol, threonine and povidone, wherein the mass ratio of mannitol, threonine and povidone is 7:2:1.

[0043] The preparation method of isavuconazole sulfate for injection comprises the following steps:

[0044] S1. Liquid preparation

[0045] After adding water for injection to the liquid preparation bag to about 60% of the total amount of the liquid preparation, start cooling, start the tank stirring, set the stirring speed to 200rpm, and control the water temperature to 2-8°C; when the temperature of the water for injection in the liquid preparation bag drops to 8°C or below, open the feeding port and put the weighed mannitol, threonine and povidone into the liquid preparation bag, and stir until they are completely dissolved; when the temperature of the drug solution drops to <5°C, put the weighed isavuconazole sulfate into the liquid preparation bag, rinse the weighing container with 4% of the total amount of the liquid preparation water, merge the rinse liquid into the liquid preparation bag, and then stir for 35 minutes or more until it is completely dissolved; measure the pH of the intermediate drug solution, when it is greater than 1.5, adjust the solution pH to 1.3-1.5 with 8wt% sulfuric acid solution, continue stirring for about 5 minutes, take the solution to measure the pH value, add water for injection (water temperature 10-25°C) to the full amount (control the drug solution temperature below 8°C), and continue stirring for 15 minutes;

[0046] S2, Filtration and Filling

[0047] The drug solution was initially filtered through a 0.45um filter element [size: 5 inches, material: polyethersulfone (PES), brand: Cobetter], and sterilized and filtered through two 0.2um filter elements [size: 5 inches, material: polyethersulfone (PES), brand: Cobetter], and then filled into a vial and half-stoppered;

[0048] S3. Freeze-drying

[0049] (1) Pre-cooling of the partition: before feeding the freeze dryer, the temperature of the heat transfer oil is set to 2°C;

[0050] (2) Pre-freezing: Set the temperature of the heat transfer oil to -40°C and maintain it for 3 hours. After the pre-freezing is completed, open the refrigeration box. When the temperature of the refrigeration box reaches below -50°C, start vacuuming.

[0051] (3) Sublimation drying: After the vacuum degree of the current chamber drops to ≤0.2 mbar and stabilizes, the temperature of the thermal oil is raised to 0°C at a heating rate of 0.5°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.2 mbar) and maintained for 20 hours;

[0052] (4) Desorption and drying: After the constant temperature is completed, the temperature of the heat transfer oil is increased to 35°C at a heating rate of 0.5°C / min, and a limited amount of leakage is opened (the vacuum is 0.05mbar) and maintained for 12 hours. The temperature of the heat transfer oil is reduced to 15°C at a cooling rate of 0.5°C / min, and a limited amount of leakage is opened (the vacuum is 0.05mbar). After 0.5 hours, the aeration valve is closed, and the pressure rise test is performed after 30 minutes of extreme vacuuming. The middle diaphragm valve is closed, and the vacuum change of the front box is observed. It is ≤0.02mbar within 1 minute. The operation is repeated 2 times after 5 minutes. If the test is qualified for 3 consecutive times, the freeze-drying is terminated; if it does not meet the requirements, the extreme vacuuming is continued until it is finally judged to meet the requirements of "≤0.02mbar within 1 minute";

[0053] (5) Nitrogen filling protection and full pressure plugging: When filling with nitrogen, observe that the vacuum value of the front box rises to -0.03MPa~-0.02MPa, stop the nitrogen input, let it stand for about 5 minutes, and then perform the full pressure plugging operation on the product.

[0054] Example 3

[0055] Disclosed isavuconazole sulfate for injection comprises the following raw materials and auxiliary materials, measured by weight: 40 parts of isavuconazole sulfate, 10 parts of excipients, an appropriate amount of 8wt% sulfuric acid solution (adjusting the pH to 1.3-1.5), and 400 parts of water for injection; the excipients are mannitol, threonine and povidone, wherein the mass ratio of mannitol, threonine and povidone is 8:1:1.

[0056] The preparation method of isavuconazole sulfate for injection comprises the following steps:

[0057] S1. Liquid preparation

[0058] After adding water for injection to the liquid preparation bag to about 70% of the total amount of the liquid preparation, start cooling, start the tank stirring, set the stirring speed to 200rpm, and control the water temperature to 2-8°C; when the temperature of the water for injection in the liquid preparation bag drops to 8°C or below, open the feeding port and put the weighed mannitol, threonine and povidone into the liquid preparation bag, and stir until they are completely dissolved; when the temperature of the drug solution drops to <5°C, put the weighed isavuconazole sulfate into the liquid preparation bag, rinse the weighing container with 4% of the total amount of the liquid preparation water, merge the rinse liquid into the liquid preparation bag, and then stir for 35 minutes or more until it is completely dissolved; measure the pH of the intermediate drug solution, when it is greater than 1.5, adjust the solution pH to 1.3-1.5 with 8wt% sulfuric acid solution, continue stirring for about 5 minutes, take the solution to measure the pH value, add water for injection (water temperature 10-25°C) to the full amount (control the drug solution temperature below 8°C), and continue stirring for 15 minutes;

[0059] S2, Filtration and Filling

[0060] The drug solution was initially filtered through a 0.45um filter element [size: 5 inches, material: polyethersulfone (PES), brand: Cobetter], and sterilized and filtered through two 0.2um filter elements [size: 5 inches, material: polyethersulfone (PES), brand: Cobetter], and then filled into a vial and half-stoppered;

[0061] S3. Freeze-drying

[0062] (1) Pre-cooling of the partition: before feeding the freeze dryer, the temperature of the heat transfer oil is set to 2°C;

[0063] (2) Prefreezing: Set the temperature of the heat transfer oil to -50°C and maintain it for 3 hours. After the prefreezing is completed, open the refrigeration box. When the temperature of the box reaches below -50°C, start vacuuming.

[0064] (3) Sublimation drying: After the vacuum degree of the current chamber drops to ≤0.2 mbar and stabilizes, the temperature of the heat transfer oil is raised to -5°C at a heating rate of 0.3°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.2 mbar) and maintained for 20 hours;

[0065] (4) Analytical drying: After the constant temperature is completed, the temperature of the heat transfer oil is increased to 30°C at a heating rate of 0.3°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.05mbar), and maintained for 10 hours. The temperature of the heat transfer oil is reduced to 10°C at a cooling rate of 0.5°C / min, and a limited amount of leakage is opened at the same time (the vacuum is set to 0.05mbar). After 0.5 hours, the aeration valve is closed, and the pressure rise test is performed after 30 minutes of extreme vacuuming. The middle diaphragm valve is closed, and the vacuum changes in the front box are observed. The vacuum is ≤0.02mbar within 1 minute. Repeat this operation 2 more times after an interval of 5 minutes. If the test is qualified for 3 consecutive times, the freeze-drying is terminated; if it does not meet the requirements, the extreme vacuuming is continued until it is finally judged to meet the "≤0.02mbar within 1 minute";

[0066] (5) Nitrogen filling protection and full pressure plugging: When filling with nitrogen, observe that the vacuum value of the front box rises to -0.03MPa~-0.02MPa, stop the nitrogen input, let it stand for about 5 minutes, and then perform the full pressure plugging operation on the product.

[0067] Comparative Example 1

[0068] The difference between this example and Example 2 is that the excipient in this example does not contain threonine, and the missing amount of threonine is distributed in mannitol and povidone according to the corresponding proportion.

[0069] The preparation process of isavuconazole sulfate for injection is basically the same as that in Example 2.

[0070] Comparative Example 2

[0071] The difference between this example and Example 2 is that the excipient in this example does not contain povidone, and the missing amount of povidone is distributed in the corresponding proportions to mannitol and threonine.

[0072] The preparation process of isavuconazole sulfate for injection is basically the same as that in Example 2.

[0073] Comparative Example 3

[0074] The difference between this example and Example 2 is that the mass ratio of mannitol, threonine and povidone in the excipients of this example is 5:4:1.

[0075] The preparation process of isavuconazole sulfate for injection is basically the same as that in Example 2.

[0076] Comparative Example 4

[0077] The difference between this example and Example 2 is that threonine in the excipient of this example is replaced by glycine.

[0078] The preparation process of isavuconazole sulfate for injection is basically the same as that in Example 2.

[0079] Comparative Example 5

[0080] The difference between this example and Example 2 is that threonine in the excipient of this example is replaced by aspartic acid.

[0081] The preparation process of isavuconazole sulfate for injection is basically the same as that in Example 2.

[0082] Comparative Example 6

[0083] The difference between this example and Example 2 is that the povidone in the excipient of this example is replaced by polyvinyl alcohol.

[0084] The preparation process of isavuconazole sulfate for injection is basically the same as that in Example 2.

[0085] Experimental example

[0086] The isavuconazole sulfate for injection prepared in Examples 1-3 and Control Examples 1-6 and the reference preparation Kangxinbo isavuconazole sulfate for injection were stored for a long time (0-3 months) at a temperature of 2-8°C, under strong light illumination (4500Lx±500Lx) for 10 days, and accelerated (25°C / 75%RH) for 30 days according to the Chinese Pharmacopoeia Volume IV (2020 edition). The relevant properties were investigated under different treatment conditions, and the test results are shown in Table 1.

[0087] Table 1

[0088]

[0089]

[0090]

[0091] The test results show that the stability of the isavuconazole sulfate for injection prepared in Examples 1-3 of the present invention under different treatment conditions such as long-term storage (0-3 months) at a temperature of 2-8°C, strong light illumination (4500Lx±500Lx) for 10 days, and accelerated (25°C / 75%RH) for 30 days is significantly better than that of Comparative Examples 1-6, especially the stability under strong light illumination for 10 days and accelerated (25°C / 75%RH) for 30 days is better than that of commercially available products.

[0092] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An isavuconazole sulfate for injection, characterized in that: The invention comprises the following raw materials and auxiliary materials by weight: 30-40 parts of isavuconazole sulfate, 6-10 parts of excipients, an appropriate amount of sulfuric acid solution (adjusting the pH value to 1.3-1.5), and 300-400 parts of water for injection; the excipients are mannitol, threonine and povidone.

2. The isavuconazole sulfate for injection according to claim 1, characterized in that: The mass ratio of mannitol, threonine and povidone in the excipient is (6-8):(1-2):(1-2).

3. The isavuconazole sulfate for injection according to claim 1, characterized in that: The sulfuric acid solution is an 8 wt % sulfuric acid solution.

4. The process of preparing isavuconazole sulfate for injection according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Liquid preparation: After adding water for injection to the liquid preparation container to 50-70% of the total amount of the liquid preparation, control the water temperature at 2-8°C. When the temperature of the water for injection drops to 8°C or below, add the weighed mannitol, threonine and povidone into the liquid preparation container and stir until they are completely dissolved. When the temperature of the liquid drops to <5°C, add the weighed isavuconazole sulfate into the liquid preparation container and stir until it is completely dissolved. Subsequently, adjust the pH value of the solution to 1.3-1.5 with sulfuric acid solution and replenish the water for injection; S2, filtration and filling: the drug solution is filtered through a microporous filter membrane and then divided into vials, which are semi-stoppered to obtain a freeze-dried drug solution; S3. Freeze-drying: freeze-dry the drug solution to be freeze-dried, then perform nitrogen protection and full plugging to obtain isavuconazole sulfate for injection.

5. The process of preparing isavuconazole sulfate for injection according to claim 4, characterized in that: The step S2 of filtering with a microporous filter membrane specifically comprises: initially filtering the drug solution through a 0.45um filter element, and then filtering it through two 0.2um filter elements for sterilization; the filter element is made of polyethersulfone.

6. The process of preparing isavuconazole sulfate for injection according to claim 4, characterized in that: The S3 freeze-drying specifically comprises the following steps: (1) Pre-cooling of the partition: Before feeding the freeze dryer, set the temperature of the heat transfer oil to 0-2°C; (2) Pre-freezing: Set the temperature of the heat transfer oil to -50 to -40°C, keep it warm for 2 to 3 hours, and after the pre-freezing is completed, open the refrigeration box. When the temperature of the box reaches below -50°C, start vacuuming. (3) Sublimation drying: After the vacuum degree of the current chamber drops to ≤0.2 mbar and stabilizes, raise the temperature of the thermal oil to -5 to 5°C and maintain it for 15 to 20 hours; (4) Desorption and drying: After the constant temperature is completed, the temperature of the heat transfer oil is raised to 30-40°C and maintained for 10-15 hours, and then the temperature of the heat transfer oil is lowered to 10-20°C. After the ultimate vacuum is drawn for 20-30 minutes, a pressure rise test is performed to determine the freeze-drying endpoint; (5) Nitrogen filling protection and full pressure plugging: When filling with nitrogen, observe that the vacuum value of the front box rises to -0.03MPa~-0.02MPa, stop the nitrogen input, let it stand for 3~5 minutes, and then perform the full pressure plugging operation on the product.

7. The process of preparing isavuconazole sulfate for injection according to claim 4, characterized in that: The heating rate of the heat transfer oil in the sublimation drying and analytical drying is 0.3°C / min to 0.5°C / min; the cooling rate of the heat transfer oil in the analytical drying is 0.3°C / min to 0.5°C / min.

8. The process of preparing isavuconazole sulfate for injection according to claim 4, characterized in that: The pressure rise test for judging the freeze-drying endpoint is specifically as follows: close the septum valve, observe the vacuum change in the front box, and the vacuum should be ≤0.02 mbar within 1 minute. Repeat this operation 2 more times after an interval of 5 minutes. If the test is passed 3 times in a row, the freeze-drying is terminated. If the test does not meet the requirements, continue to evacuate the vacuum to the limit until it is finally judged to meet the requirements of "≤0.02 mbar within 1 minute".

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