A freeze-drying method for a lyophilized product of levonikkomycin disodium phosphate for injection

Abstract

The present application relates to the technical field of chemical medicine preparation, and particularly discloses a freeze-drying method of injection phosphonic acid left-onitrazole ester disodium freeze-dried product. The present application pre-freezes phosphonic acid left-onitrazole ester disodium liquid at-20℃ to-15℃, freezes the obtained suspension material at-60℃ to-40℃ to obtain frozen solid, sublimates and dries the frozen solid at-12℃ to-8℃, and analyzes and dries at 15℃ to 25℃ to obtain injection phosphonic acid left-onitrazole ester disodium freeze-dried product. In the pre-freezing stage, the phosphonic acid left-onitrazole ester disodium liquid gradually changes from liquid to suspension material with uniform solute, and the solute is not frozen solid; in the freezing stage, the suspension material is gradually frozen solid; in the sublimation drying stage, the free water in the material is removed by one-stage heating, which greatly shortens the freeze-drying time; finally, the bound water in the material is removed in the analysis stage, and the moisture and impurity content in the freeze-dried product are lower.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical drug preparations, in particular to a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection. Background Art

[0002] Levoornidazole disodium phosphate is the sodium salt of the phosphate derivative of the L-isomer of ornidazole. It belongs to the nitroimidazole antibiotic class and is primarily used to treat severe amebiasis of the intestine and liver, postoperative infections caused by ornidazole-sensitive anaerobic bacteria, and prevent surgical-induced infections caused by sensitive anaerobic bacteria. Levoornidazole disodium phosphate is a prodrug of levornidazole. Pharmacokinetic studies have shown that levornidazole disodium phosphate rapidly decomposes into levornidazole in the body. Compared to levornidazole, salified levornidazole disodium phosphate offers the following advantages: enhanced lipophilicity, significantly reduced toxicity, and prolonged drug metabolism. It also addresses the poor water solubility of ornidazole, eliminating the need for cosolvents and other excipients in the injectable formulation, allowing for direct lyophilization. This reduces the adverse reaction rate and significantly increases bioavailability. The injectable pH is closer to neutral, reducing patient pain during intravenous infusion.

[0003] The existing freeze-drying method for the freeze-dried product of levonidazole disodium phosphate for injection is complex and requires frequent temperature increase and decrease. The sublimation time in one sublimation drying stage is long, resulting in a long overall freeze-drying time, low production efficiency, and high production costs. Summary of the Invention

[0004] In response to the above problems, the present invention provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection. The present invention improves the quality of the freeze-dried product of levornidazole disodium phosphate for injection by controlling the conditions of pre-freezing, freezing, sublimation drying and analytical drying. The method is simple to operate, shortens the freeze-drying time, improves production efficiency, and saves production costs.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] A freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection comprises the following steps:

[0007] S1, pre-freezing the levornidazole disodium phosphate solution at -20°C to -15°C, and then freezing the resulting suspension at -60°C to -40°C to obtain a frozen solid;

[0008] S2, performing sublimation drying on the frozen solid at -12°C to -8°C, and then performing desorption drying at 15°C to 25°C to obtain a freeze-dried product of levornidazole disodium phosphate for injection.

[0009] Relative to prior art, the freeze drying method of the freeze-dried product of levonidazole disodium phosphate for injection provided by the present invention, pre-freeze at a specific temperature, so that levonidazole disodium phosphate medicinal liquid is in the "supercooling" stage, levonidazole disodium phosphate medicinal liquid is progressively frozen to form freeze-dried crystals, and tiny crystals are combined with each other to form irregular large-particle crystals, and a sublimation channel is formed between the large-particle crystals, forming a larger and uniform crystal form, with a specific structure, the sublimation drying channel of moisture in the subsequent sublimation drying process is increased, and better temperature can be tolerated, which is conducive to accelerating the sublimation rate in the subsequent sublimation drying process. In the pre-freezing stage of the present invention, levonidazole disodium phosphate medicinal liquid gradually changes from a liquid state to a suspension material with uniform solute, and the solute is not frozen solid; in the freezing stage, the suspension material is progressively frozen solid; the sublimation drying stage adopts a stage to heat up, so that the free water in the material can be removed, which greatly shortens the freeze-drying time; finally, the bound water in the material is removed in the parsing stage.

[0010] The present invention provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection. The freeze-drying method comprises pre-freezing, freezing, sublimation drying, and analytical drying of a levornidazole disodium phosphate liquid at a specific temperature. The moisture content of the material is gradually reduced, thereby slowing down the degradation rate of the freeze-dried product of levornidazole disodium phosphate for injection (hereinafter referred to as the freeze-dried product) during storage. The freeze-dried product also has lower moisture and impurity contents, better stability, and higher medication safety, thereby improving the quality of existing freeze-dried products.

[0011] Preferably, in S1, the levornidazole disodium phosphate solution comprises levornidazole disodium phosphate and water for injection in a mass ratio of 1:(17-22).

[0012] Preferably, in S1, the pH of the levornidazole disodium phosphate solution is 5-5.5.

[0013] The present invention adopts conventional pH regulator to adjust the pH of levornidazole disodium phosphate solution within the above range.

[0014] For example, the levornidazole disodium phosphate solution can be filled, and the dosage can be 2.5 mL / vial.

[0015] Preferably, in S1, the temperature is lowered to -20°C to -15°C by programmed cooling, with a cooling rate of 0.8°C / min to 1.2°C / min.

[0016] Preferably, in S1, the pre-freezing time is 50 min to 70 min.

[0017] By limiting the pre-freezing conditions, the present invention can ensure that the levornidazole disodium phosphate liquid is fully crystallized at a specific temperature, ensure that the solute (water for injection) in the obtained suspension material is evenly mixed and the solute is uniform, which is conducive to controlling the structure of the crystals.

[0018] Preferably, in S1, the temperature is lowered to -60°C to -40°C by programmed cooling, with a cooling rate of 0.8°C / min to 1.2°C / min.

[0019] Preferably, in S1, the freezing time is 100 min to 130 min.

[0020] The present invention can ensure that the suspension material with a specific structure formed in the pre-freezing stage is gradually frozen solid by limiting the freezing conditions, which is beneficial to subsequent operations.

[0021] Preferably, in S2, the temperature is raised to -12°C to -8°C by programmed heating, and the heating time is 50 min to 70 min.

[0022] Preferably, in S2, the vacuum degree of the sublimation drying is 0.35 mbar to 0.45 mbar, and the sublimation drying time is 9 h to 11 h.

[0023] The present invention controls the sublimation drying conditions and adopts only one stage design to ensure that free water in the material is removed, thereby greatly shortening the time of the existing sublimation drying stage, improving production efficiency and saving production costs.

[0024] Preferably, in S2, the temperature is raised to 15°C to 25°C by programmed heating, with a heating rate of 0.8°C / min to 1.2°C / min.

[0025] Preferably, in S2, the vacuum degree of the analytical drying is 0.35 mbar to 0.45 mbar, and the time of the analytical drying is 2.5 h to 3.5 h.

[0026] The present invention can further ensure that the bound water in the material is effectively removed by controlling the conditions of analytical drying. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figures 1 and 2 This is an appearance diagram of the freeze-dried product of levornidazole disodium phosphate for injection in Example 1 of the present invention. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0029] Example 1

[0030] This embodiment provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, comprising the following steps:

[0031] Sa, prepare levornidazole disodium phosphate solution:

[0032] Weigh 450 mL of water for injection into a beaker, add 25 g of the raw material levornidazole disodium phosphate, mix evenly, add a pH adjuster to adjust the pH of the levornidazole disodium phosphate solution to 5.2, then adjust the volume to 500 mL, fill according to the filling volume of 2.5 mL / tube, fill 200 tubes, and obtain the levornidazole disodium phosphate solution, half-stopper it and transfer it into the freeze dryer.

[0033] Sb, the levornidazole disodium phosphate solution was cooled to -18°C at a rate of 1°C / min for pre-freezing and kept warm for 60 minutes; then the resulting suspension material was cooled to -50°C at a rate of 1°C / min for freezing and kept warm for 120 minutes to obtain a frozen solid.

[0034] Sc, the frozen solid was heated to -10°C for sublimation drying in 60 minutes, the vacuum degree was 0.4 mbar, and the temperature was kept warm for 10 hours; then the temperature was heated to 20°C at a rate of 1°C / min for desorption drying, the vacuum degree was 0.4 mbar, and the temperature was kept warm for 3 hours to obtain the freeze-dried product of levornidazole disodium phosphate for injection.

[0035] The total freeze-drying time of Sb~Sc is about 22 hours. The appearance of the obtained freeze-dried product of levonidazole disodium phosphate for injection is loose white blocks (see Figures 1 and 2 ).

[0036] Example 2

[0037] This embodiment provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, comprising the following steps:

[0038] Sa, prepare levornidazole disodium phosphate solution:

[0039] Weigh 450 mL of water for injection into a beaker, add 25 g of the raw material levornidazole disodium phosphate, mix evenly, add a pH adjuster to adjust the pH of the levornidazole disodium phosphate solution to 5.5, then adjust the volume to 500 mL, fill it at a volume of 2.5 mL / vial, fill 200 vials, and obtain the levornidazole disodium phosphate solution. Half-stopper it and transfer it into the freeze dryer.

[0040] Sb, the levornidazole disodium phosphate solution was cooled to -20°C at a rate of 0.8°C / min for pre-freezing and kept warm for 50 minutes; then the resulting suspension material was cooled to -60°C at a rate of 0.8°C / min for freezing and kept warm for 100 minutes to obtain a frozen solid.

[0041] Sc, the frozen solid was heated to -12°C for sublimation drying in 50 minutes, the vacuum degree was 0.45 mbar, and the temperature was kept warm for 9 hours; then the temperature was heated to 15°C at a rate of 0.8°C / min for desorption drying, the vacuum degree was 0.45 mbar, and the temperature was kept warm for 2.5 hours to obtain the freeze-dried product of levonidronate disodium phosphate for injection.

[0042] According to calculation, the total time of the freeze-drying process of Sb~Sc is about 21 hours, and the appearance of the obtained freeze-dried product of levonidazole disodium phosphate for injection is loose white blocks.

[0043] Example 3

[0044] This embodiment provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, comprising the following steps:

[0045] Sa. Preparation of levornidazole disodium phosphate solution: same as in Example 1, no further details will be given.

[0046] Sb, the levornidazole disodium phosphate solution was cooled to -15°C at a rate of 1.2°C / min for pre-freezing and kept warm for 70 minutes; then the resulting suspension material was cooled to -40°C at a rate of 1.2°C / min for freezing and kept warm for 130 minutes to obtain a frozen solid.

[0047] Sc, the frozen solid was heated to -8°C for sublimation drying at a vacuum degree of 0.35 mbar for 11 hours; then heated to 25°C at a rate of 1.2°C / min for desorption drying at a vacuum degree of 0.35 mbar for 3.5 hours to obtain the freeze-dried product of levornidazole disodium phosphate for injection.

[0048] According to calculation, the total time of the freeze-drying process of Sb~Sc is about 23 hours, and the appearance of the obtained freeze-dried product of levornidazole disodium phosphate for injection is loose white blocks.

[0049] Comparative Example 1

[0050] This comparative example provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, which is similar to Example 1, except that in Example Sb, the pre-freezing stage is omitted, and the levornidazole disodium phosphate solution is directly frozen under freezing conditions. Specifically, the method comprises the following steps:

[0051] Sa. Preparation of levornidazole disodium phosphate solution: same as in Example 1, no further details will be given.

[0052] Sb, the levornidazole disodium phosphate solution was cooled to -40°C at a rate of 1.2°C / min and kept warm for 200 minutes to obtain a frozen solid.

[0053] Sc, same as embodiment 1, no further details are given.

[0054] Comparative Example 2

[0055] This comparative example provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, which is similar to Example 1, except that the pre-freezing temperature in Sb is -6°C. The remaining conditions are the same as in Example 1 and are not described again.

[0056] Comparative Example 3

[0057] This comparative example provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, which is similar to that of Example 1, except that the freezing temperature in Sb is -30° C. The remaining conditions are the same as those in Example 1 and will not be repeated here.

[0058] Comparative Example 4

[0059] This comparative example provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, which is similar to that of Example 1, except that the sublimation drying temperature in Sc is 0° C. The remaining conditions are the same as those in Example 1 and are not described again.

[0060] Examples 1 to 3 of the present invention, comparative examples 1 to 4, and commercially available freeze-dried products of levornidazole disodium phosphate for injection were tested for moisture and impurities, and the specific results are shown in Table 1. The commercially available freeze-dried products of levornidazole disodium phosphate for injection were purchased from Jiangsu Zilong Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group with batch number 23062051.

[0061] Table 1 Test results of Examples, Comparative Examples and commercially available freeze-dried products

[0062]

[0063] It can be seen from the test results of the embodiments of the present invention and the commercially available freeze-dried products that the appearance of the freeze-dried product of levornidazole disodium phosphate for injection provided by the present invention is consistent with the commercially available freeze-dried product, both of which are loose white blocks, and the moisture and impurity contents are significantly lower than the commercially available freeze-dried products, that is, the freeze-dried product of levornidazole disodium phosphate for injection provided by the present invention is of better quality. It can be seen from the test results of the freeze-dried product of levornidazole disodium phosphate for injection of the embodiments of the present invention and the comparative example that after changing the conditions of pre-freezing, freezing or sublimation drying, the quality of the freeze-dried product of levornidazole disodium phosphate for injection obtained is greatly reduced.

[0064] 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 or improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, characterized in that: The following steps are involved: S1, pre-freezing the levornidazole disodium phosphate solution at -20°C to -15°C, and then freezing the resulting suspension at -60°C to -40°C to obtain a frozen solid; The levornidazole disodium phosphate solution comprises levornidazole disodium phosphate and water for injection in a mass ratio of 1:(17-22); the pH value of the levornidazole disodium phosphate solution is 5.2-5.5; The temperature is lowered to -20°C to -15°C by programmed cooling at a rate of 0.8°C / min to 1.2°C / min; the pre-freezing time is 50min to 70min; The temperature is lowered to -60°C to -40°C by programmed cooling at a rate of 0.8°C / min to 1.2°C / min; the freezing time is 100min to 130min; S2, sublimation drying the frozen solid at -12°C to -8°C, and then desorption drying at 15°C to 25°C to obtain a freeze-dried product of levornidazole disodium phosphate for injection; The temperature is raised to -12°C~-8°C by programmed heating, and the heating time is 50min~70min; the vacuum degree of the sublimation drying is 0.35mbar~0.45mbar, and the sublimation drying time is 9h~11h; The temperature is raised to 15°C~25°C by programmed heating, with a heating rate of 0.8°C / min~1.2°C / min; the vacuum degree of the analytical drying is 0.35mbar~0.45mbar, and the analytical drying time is 2.5h~3.5h.

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