Lyophilization method for isavuconazole sulfate raw material

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a freeze-drying method for isavuconazole sulfate API. The method comprises: dissolving isavuconazole sulfate in purified water to obtain a liquid; pre-freezing the liquid, sublimation drying, and desorption drying to obtain freeze-dried isavuconazole sulfate API. The desorption drying process is as follows: 1) primary desorption: maintaining a vacuum of 5-15 Pa, adjusting the temperature to 5-15°C, and maintaining the temperature for 3-8 hours; 2) secondary desorption: adjusting the vacuum of 1-6 Pa, maintaining the temperature at 5-15°C, and maintaining the temperature for 2-7 hours. The present invention utilizes freeze-drying technology to dry the isavuconazole sulfate aqueous solution. The resulting isavuconazole sulfate API has low impurity content, low moisture content, a loose product texture, and high stability, making it more suitable for downstream preparation into capsules, powder injections, and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a freeze-drying method for isavuconazole sulfate raw material medicine. Background Art

[0002] Isavuconazonium sulfate is a triazole antifungal drug jointly developed by Astellas (Japan) and Basilea (Switzerland). The drug was first approved by the U.S. Food and Drug Administration (FDA) in 2015, granting it Qualified Infectious Disease Product (QIDP) designation for azole antifungals and orphan drug designation for the treatment of invasive aspergillosis and invasive mucormycosis. These two diseases are serious infections caused by different types of molds and typically affect patients with compromised immune systems, such as cancer patients, organ transplant recipients, or individuals taking long-term immunosuppressants. Isavuconazonium sulfate inhibits the synthesis of ergosterol, a key component of fungal cell membranes, thereby preventing fungal growth and reproduction. This mechanism of action makes it an effective broad-spectrum antifungal drug. As of 2024, the drug has been approved for use in over 60 countries and regions worldwide, including the United States, the European Union, Japan, and China.

[0003] The chemical structural formula of isavuconazole sulfate is shown in Formula I.

[0004] Ⅰ.

[0005] Some prior art reports on the preparation processes of isavuconazole sulfate. For example, Hainan Weikang's patent CN119488486A discloses a lyophilized powder injection of isavuconazole sulfate and its preparation method. This lyophilized powder injection comprises, in addition to the main ingredient, 70-80 wt% isavuconazole sulfate, excipients such as mannitol, sorbitol, and sucrose, and water for injection. Hainan Guangshengyu's patent CN119523918A also discloses a lyophilized preparation of isavuconazole sulfate for injection and its preparation method. This lyophilized preparation of isavuconazole sulfate for injection comprises, in addition to the main ingredient, lyoprotectants (mannitol and lactose), a pH adjuster (sulfuric acid), and water for injection. These patents all disclose lyophilization methods for isavuconazole sulfate powder injection. The preparation consists of the isavuconazole sulfate API as the main ingredient, excipients, pH adjusters, and water for injection, and then lyophilized to produce a finished preparation for direct patient use. The freeze-drying process for isavuconazole sulfate API is different. To ensure that the isavuconazole sulfate API meets the pharmacopoeia requirements for residual solvents and content, the chemically synthesized isavuconazole sulfate must undergo a series of purification steps. The resulting freeze-dried liquid contains only isavuconazole sulfate and purified water, without the need for other excipients.

[0006] A search of the literature on isavuconazole sulfate API revealed that Yangtze River Group's CN106916152A patent and CN115215857A patent, Jiangsu Aosaikang's CN106467534A patent, and Borri Pharmaceutical (Suzhou)'s CN117510488A patent all obtained isavuconazole sulfate through freeze-drying, but none of these patents disclosed the freeze-drying process for isavuconazole sulfate API.

[0007] Therefore, it is necessary to develop a freeze-drying method for isavuconazole sulfate raw material to fill the gap in the existing technology in this field. Summary of the Invention

[0008] In view of this, one of the objects of the present invention is to provide a freeze-drying method for isavuconazole sulfate raw material. The product prepared by the freeze-drying process of the present invention has good properties, low moisture content and high stability.

[0009] To achieve the above object, the present invention adopts the following technical solutions:

[0010] A freeze-drying method for isavuconazole sulfate raw material medicine comprises dissolving isavuconazole sulfate in purified water to obtain a feed liquid; and pre-freezing, sublimation drying and analytical drying of the feed liquid to obtain freeze-dried isavuconazole sulfate raw material medicine;

[0011] The analytical drying setting is as follows:

[0012] 1) Primary analysis: Maintain vacuum at 5-15 Pa, adjust temperature to 5-15°C, and keep warm for 4-8 hours;

[0013] 2) Secondary analysis: Adjust the vacuum degree to 1-6 Pa, maintain the temperature at 5-15°C, and keep warm for 3-7 hours.

[0014] Furthermore, the mass ratio of the isavuconazole sulfate to the purified water is 1:7-10.

[0015] Preferably, the mass ratio of the isavuconazole sulfate to the purified water is 1:8-9.

[0016] Preferably, the freeze-drying of the isavuconazole sulfate bulk drug is carried out in a freeze-drying tray.

[0017] Preferably, the preparation of the isavuconazole sulfate aqueous solution specifically comprises: mixing isavuconazole sulfate and purified water in proportion, cooling to 3-10° C., and filtering to obtain the isavuconazole sulfate solution.

[0018] More preferably, isavuconazole sulfate is mixed with purified water and then cooled to 5°C.

[0019] More preferably, during sample preparation, filtration is performed once using a 0.45 μm filter membrane.

[0020] Furthermore, the pre-freezing includes: cooling to -5 to 2°C and keeping warm for 20 to 50 minutes; adjusting the temperature to -30 to -50°C and keeping warm for 1 to 3 hours.

[0021] Furthermore, during the pre-freezing, the temperature is adjusted to -30 to -50°C using a cooling rate of 15 to 25°C / h.

[0022] As a preferred solution, the pre-freezing includes: cooling to -2 to 2°C and keeping warm for 30 minutes; adjusting the temperature to -38 to -42°C at a cooling rate of 18 to 22°C / h and keeping warm for 1.5 to 2.5 hours.

[0023] Further, the sublimation drying is set as follows:

[0024] 1) Primary sublimation: adjust the vacuum degree to 15-25 Pa, adjust the temperature to -10-20°C, and keep warm for 2-10 hours;

[0025] 2) Secondary sublimation: adjust the vacuum degree to 5-15 Pa, adjust the temperature to 0-15°C, and keep warm for 4-10 hours.

[0026] Furthermore, the temperature of the primary sublimation is adjusted to -10 to -20°C at a heating rate of 10 to 20°C / h; and the temperature of the secondary sublimation is adjusted to 0 to -15°C at a heating rate of 5 to 15°C / h.

[0027] As a preferred solution, the sublimation drying is set as follows:

[0028] 1) Primary sublimation: adjust the vacuum degree to 16~20Pa, adjust the temperature to -13~-17℃ at a heating rate of 11~15℃ / h, and keep warm for 3~5h;

[0029] 2) Secondary sublimation: Adjust the vacuum degree to 8~12Pa, adjust the temperature to -3~-7℃ at a heating rate of 8~10℃ / h, and keep warm for 5~7h.

[0030] Furthermore, in the first analysis, the temperature is adjusted to 5-15° C. using a heating rate of 5-15° C. / h.

[0031] Preferably, the analytical drying is set as follows:

[0032] 1) Primary analysis: Maintain a vacuum of 8-12 Pa, adjust the temperature to 8-12°C at a heating rate of 8-10°C / h, and keep warm for 4-6 hours;

[0033] 2) Secondary analysis: Adjust the vacuum degree to 2~4Pa, keep the temperature constant, and keep warm for 3~5h.

[0034] As a preferred solution, the freeze-drying method specifically comprises the following steps:

[0035] (1) Preparation of liquid

[0036] dissolving isavuconazole sulfate in purified water to obtain a feed solution;

[0037] (2) Pre-freezing

[0038] The liquid obtained in step (1) is added to a freeze-drying tray for pre-freezing; the pre-freezing conditions include: cooling to -2 to 2°C and keeping warm for 30 minutes; adjusting the temperature to -38 to -42°C at a cooling rate of 18 to 22°C / h and keeping warm for 1.5 to 2.5 hours;

[0039] (3) Sublimation drying

[0040] Primary sublimation: adjust the vacuum degree to 16~20Pa, adjust the temperature to -13~-17℃ at a heating rate of 11~15℃ / h, and keep warm for 3~5h;

[0041] Secondary sublimation: adjust the vacuum degree to 8~12Pa, adjust the temperature to -3~-7℃ at a heating rate of 8~10℃ / h, and keep warm for 5~7h;

[0042] (4) Analytical drying

[0043] Primary analysis: maintain the vacuum degree at 8-12 Pa, adjust the temperature to 8-12°C at a heating rate of 8-10°C / h, and keep warm for 4-6 hours;

[0044] Secondary analysis: adjust the vacuum degree to 2-4 Pa, maintain the temperature at 8-12°C, and keep warm for 3-5 hours to obtain freeze-dried isavuconazole sulfate raw material.

[0045] The beneficial effects of the present invention are:

[0046] 1. The present invention uses a specific freeze-drying process to effectively remove moisture from the isavuconazole sulfate raw material, reduce the growth of impurities and microorganisms, and improve the stability of the product.

[0047] 2. In the present invention, the liquid obtained by freeze-drying isavuconazole sulfate and purified water in a mass ratio of 1:7-9 is obtained. The resulting finished product is a loose white block, which is convenient for post-processing by the preparation side.

[0048] 3. The quality of isavuconazole sulfate is greatly affected by temperature. The freeze-drying temperature requirement is low, which effectively avoids the destruction of isavuconazole sulfate by higher temperatures. The resulting product has low impurities and high stability. DETAILED DESCRIPTION

[0049] The technical solutions of the present invention will be further described in detail below with reference to specific embodiments. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Therefore, all other embodiments derived by those skilled in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0050] Example 1. A freeze-drying method for isavuconazole sulfate raw material

[0051] (1) Preparation of liquid

[0052] Isavuconazole sulfate and purified water were prepared into an isavuconazole sulfate aqueous solution in a mass ratio of 1:8, and the temperature was lowered to 5°C; the solution was filtered once using a 0.45 μm filter membrane, and the solution was added to a freeze-drying plate after the filtration was completed.

[0053] (2) Pre-freezing

[0054] After the feeding is completed, the partition is cooled to 0°C and kept warm for 30 minutes. The temperature is adjusted to -40°C at a cooling rate of 20°C / h and the holding time is 2 hours.

[0055] (3) Sublimation drying

[0056] Primary sublimation: adjust the vacuum degree to 18 Pa, adjust the temperature to -15°C at a cooling rate of 13°C / h, and keep warm for 4 hours.

[0057] Secondary sublimation: adjust the vacuum degree to 10 Pa, adjust the temperature to -5°C at a cooling rate of 9°C / h, and keep warm for 6 hours.

[0058] (4) Analytical drying

[0059] Primary analysis: maintain the vacuum degree at 10 Pa, adjust the temperature to 10°C at a cooling rate of 9°C / h, and keep warm for 5 hours.

[0060] Secondary analysis: Adjust the vacuum to 3 Pa, maintain the temperature at 10°C, and hold for 4 hours. Powder is obtained to obtain the isavuconazole sulfate API.

[0061] Example 2

[0062] (1) Preparation of liquid

[0063] Isavuconazole sulfate and purified water were prepared into an isavuconazole sulfate aqueous solution in a mass ratio of 1:7, and the temperature was lowered to 5°C; the solution was filtered once using a 0.45 μm filter membrane, and the solution was added to a freeze-drying plate after the filtration was completed.

[0064] (2) Pre-freezing

[0065] After the feeding was completed, the partition was cooled to 0°C and kept warm for 30 minutes. The temperature was adjusted to -38°C at a cooling rate of 18°C / h and the holding time was 1.5 hours.

[0066] (3) Sublimation drying

[0067] Primary sublimation: adjust the vacuum degree to 16 Pa, adjust the temperature to -13°C at a cooling rate of 11°C / h, and keep warm for 3 hours.

[0068] Secondary sublimation: adjust the vacuum degree to 8 Pa, adjust the temperature to -3°C at a cooling rate of 8°C / h, and keep warm for 5 h.

[0069] (4) Analytical drying

[0070] Primary analysis: maintain the vacuum degree at 8 Pa, adjust the temperature to 8°C at a cooling rate of 8°C / h, and keep warm for 4 hours.

[0071] Secondary analysis: Adjust the vacuum to 2 Pa, maintain the temperature at 8°C, and hold for 3 hours. Powder is obtained as isavuconazole sulfate API.

[0072] Example 3

[0073] (1) Preparation of liquid

[0074] Isavuconazole sulfate and purified water were prepared into an isavuconazole sulfate aqueous solution in a mass ratio of 1:9, and the temperature was lowered to 5°C; the solution was filtered once using a 0.45 μm filter membrane, and the solution was added to a freeze-drying plate after the filtration was completed.

[0075] (2) Pre-freezing

[0076] After the feeding was completed, the partition was cooled to 2°C and kept warm for 30 minutes. The temperature was adjusted to -42°C at a cooling rate of 22°C / h and the holding time was 2.5 hours.

[0077] (3) Sublimation drying

[0078] Primary sublimation: adjust the vacuum degree to 20 Pa, adjust the temperature to -17°C at a cooling rate of 15°C / h, and keep warm for 5 hours.

[0079] Secondary sublimation: adjust the vacuum degree to 12 Pa, adjust the temperature to -7°C at a cooling rate of 9°C / h, and keep warm for 7 hours.

[0080] (4) Analytical drying

[0081] Primary analysis: maintain the vacuum degree at 12 Pa, adjust the temperature to 12°C at a cooling rate of 9°C / h, and keep warm for 6 hours.

[0082] Secondary analysis: Adjust the vacuum to 4 Pa, maintain the temperature at 12°C, and hold for 5 hours. Powder is obtained as isavuconazole sulfate API.

[0083] Comparative Example 1

[0084] Based on Example 1, the ratio of "isavuconazole sulfate: purified water" in the raw material solution was adjusted as follows:

[0085] Isavuconazole sulfate and purified water were prepared into an isavuconazole sulfate aqueous solution in a mass ratio of 1:12, and the temperature was lowered to 5° C. The solution was filtered once using a 0.45 μm filter membrane. After the filtration, the solution was added to a freeze-drying plate and post-processed according to Example 1 to obtain the isavuconazole sulfate bulk drug.

[0086] Comparative Example 2

[0087] Based on Example 1, the time for primary and secondary drying was adjusted as follows:

[0088] (1) Complete the steps of "preparing the liquid", "pre-freezing" and "sublimation drying" according to Example 1.

[0089] (2) Analytical drying:

[0090] Primary analysis: maintain the vacuum degree at 10 Pa, adjust the temperature to 10°C at a cooling rate of 9°C / h, and keep warm for 3 hours.

[0091] Secondary analysis: Adjust the vacuum to 3 Pa, maintain the temperature at 10°C, and hold for 2 hours. Powder is obtained to obtain the isavuconazole sulfate API.

[0092] Comparative Example 3

[0093] Based on Example 1, the temperatures of the primary and secondary drying processes were adjusted as follows:

[0094] (1) Complete the steps of "preparing the liquid", "pre-freezing" and "sublimation drying" according to Example 1.

[0095] (2) Analytical drying:

[0096] Primary analysis: maintain the vacuum degree at 10 Pa, adjust the temperature to 25°C at a cooling rate of 9°C / h, and keep warm for 5 hours.

[0097] Secondary analysis: Adjust the vacuum to 3 Pa, maintain the temperature at 25°C, and hold for 4 hours. Powder is obtained to obtain the isavuconazole sulfate API.

[0098] Example 4. Moisture and shape testing of isavuconazole sulfate bulk drug

[0099] The isavuconazole sulfate bulk drug substances prepared in Examples 1 to 3 and Comparative Examples 1 to 3 were tested for moisture and shape, respectively.

[0100] The test results are shown in Table 1.

[0101] Table 1. Moisture and shape test results of isavuconazole sulfate API

[0102]

[0103] The results in Table 1 indicate that the isavuconazole sulfate API produced by the freeze-drying process of the present invention is a loose, white, lumpy substance. The finished product prepared by low-temperature drying has low impurities and a low moisture content, which facilitates long-term storage and reduces the growth of impurities and microorganisms. The loose nature of the finished product facilitates post-processing of the isavuconazole sulfate API by the formulation manufacturer.

[0104] Comparative Example 1, in which the ratio of "isavuconazole sulfate:purified water" in the raw material solution was adjusted, significantly increasing the proportion of purified water, resulted in a slight collapse in the finished product and a significant increase in moisture content. Comparative Example 2, in which the drying time was adjusted, reducing the primary and secondary drying times, resulted in a slight clumping of the finished product and a significant increase in moisture content. Comparative Example 3, in which the drying temperature was adjusted, increasing the primary and secondary drying temperatures, resulted in a significant increase in the maximum single impurity content in the finished product.

[0105] In summary, Examples 1 to 3 are significantly superior to the isavuconazole sulfate APIs prepared in Comparative Examples 1 to 3, and the isavuconazole sulfate APIs prepared by the present invention have excellent performance.

Claims

1. A freeze-drying method for isavuconazole sulfate bulk drug, characterized in that: Dissolving isavuconazole sulfate in purified water to obtain a liquid; pre-freezing, sublimation drying, and analytical drying the liquid to obtain lyophilized isavuconazole sulfate bulk drug; The mass ratio of the isavuconazole sulfate to the purified water is 1:7-9; The pre-freezing comprises: cooling to -5 to 2°C, keeping warm for 20 to 50 minutes; adjusting the temperature to -30 to -50°C at a cooling rate of 15 to 25°C / h, keeping warm for 1 to 3 hours; The sublimation drying is set up as follows: 1) Primary sublimation: adjust the vacuum degree to 16~20Pa, adjust the temperature to -13~-17℃ at a heating rate of 11~15℃ / h, and keep warm for 3~5h; 2) Secondary sublimation: adjust the vacuum degree to 8~12Pa, adjust the temperature to -3~-7℃ at a heating rate of 8~10℃ / h, and keep warm for 5~7h; The analytical drying setting is as follows: 1) Primary analysis: Maintain a vacuum degree of 5-15 Pa, adjust the temperature to 5-15°C at a heating rate of 5-15°C / h, and keep warm for 4-8 hours; 2) Secondary analysis: Adjust the vacuum degree to 1-6 Pa, maintain the temperature at 5-15°C, and keep warm for 3-7 hours.

2. The method according to claim 1, characterized in that The mass ratio of the isavuconazole sulfate to the purified water is 1:8-9.

3. The method according to claim 1, characterized in that The freeze-drying method specifically comprises the following steps: (1) Preparation of liquid dissolving isavuconazole sulfate in purified water to obtain a feed solution; (2) Pre-freezing The liquid obtained in step (1) is added to a freeze-drying tray for pre-freezing; the pre-freezing conditions include: cooling to -2 to 2°C and keeping warm for 30 minutes; adjusting the temperature to -38 to -42°C at a cooling rate of 18 to 22°C / h and keeping warm for 1.5 to 2.5 hours; (3) Sublimation drying Primary sublimation: adjust the vacuum degree to 16~20Pa, adjust the temperature to -13~-17℃ at a heating rate of 11~15℃ / h, and keep warm for 3~5h; Secondary sublimation: adjust the vacuum degree to 8~12Pa, adjust the temperature to -3~-7℃ at a heating rate of 8~10℃ / h, and keep warm for 5~7h; (4) Analytical drying Primary analysis: maintain the vacuum degree at 8-12 Pa, adjust the temperature to 8-12°C at a heating rate of 8-10°C / h, and keep warm for 4-6 hours; Secondary analysis: adjust the vacuum degree to 2-4 Pa, maintain the temperature at 8-12°C, and keep warm for 3-5 hours to obtain freeze-dried isavuconazole sulfate raw material.

Images