Freeze-drying method of S-ornidazole disodium phosphate freeze-dried product for injection

Abstract

The invention relates to the technical field of chemical medicine preparations, and particularly discloses a freeze-drying method of an S-ornidazole disodium phosphate freeze-dried product for injection. The preparation method comprises the following steps: pre-freezing S-ornidazole disodium phosphate liquid medicine at the temperature of-20 DEG C to-15 DEG C, and freezing an obtained suspension material at the temperature of-60 DEG C to-40 DEG C to obtain a frozen solid; and carrying out sublimation drying on the frozen solid at-12 DEG C to-8 DEG C, and carrying out desorption drying at 15 DEG C to 25 DEG C, so as to obtain the S-ornidazole disodium phosphate freeze-dried product for injection. In the pre-freezing stage, the S-ornidazole disodium phosphate liquid medicine is gradually changed into a suspension material with a uniform solute from a liquid state, and the solute is not frozen to be solid; in the freezing stage, the suspension material is gradually frozen to be compact; one-stage heating is adopted in the sublimation drying stage, so that free water in the material can be removed, and the freeze-drying time is greatly shortened; and finally, bound water in the material is removed in the analysis stage, so that the content of water and impurities in the freeze-dried product is lower.

Description

Technical Field

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

[0002] Levornidazole disodium phosphate is the sodium salt of the phosphate derivative of the levorotatory isomer of ornidazole, belonging to nitroimidazole antibiotics. It is mainly used for the treatment of severe amoebiasis in the intestine and liver, the treatment of postoperative infections caused by ornidazole-sensitive anaerobic bacteria, and the prevention of sensitive anaerobic bacteria infections caused by surgical operations. Levornidazole disodium phosphate is a prodrug of levornidazole. Pharmacokinetic studies have shown that levornidazole disodium phosphate can be rapidly decomposed into levornidazole in vivo. Compared with the function of levornidazole, levornidazole disodium phosphate has the following advantages after being salted: enhanced lipophilicity, significantly reduced toxicity, and at the same time, the drug metabolism time is prolonged; the problem of poor water solubility of ornidazole is solved, and no cosolvent and other excipients need to be added in the injection preparation, and it can be directly made into a freeze-dried preparation, reducing the adverse reaction rate of the injection, and at the same time effectively increasing the bioavailability; the pH value of the injection is closer to neutral, reducing the pain of patients during intravenous drip.

[0003] The existing freeze-drying method for the freeze-dried product of levornidazole disodium phosphate for injection has a complex process, requires frequent temperature rising and falling treatments, and has a long sublimation time in the first sublimation drying stage, resulting in a long overall freeze-drying time, low production efficiency, and high production cost. Summary of the Invention

[0004] In view of the above problems, the present invention provides a freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection. By controlling the conditions of pre-freezing, freezing, sublimation drying, and analytical drying, the present invention improves the quality of the freeze-dried product of levornidazole disodium phosphate for injection, has a simple operation, shortens the freeze-drying time, improves the production efficiency, and saves the production cost.

[0005] To solve the above technical problems, the present invention adopts the following technical solutions: A freeze-drying method for a freeze-dried product of levornidazole disodium phosphate for injection, comprising the following steps: S1, pre-freezing the levornidazole disodium phosphate medicinal solution at -20°C to -15°C, and then freezing the obtained suspension-like material at -60°C to -40°C to obtain a frozen solid; S2, performing sublimation drying on the frozen solid at -12°C to -8°C, and then performing analytical drying at 15°C to 25°C to obtain a freeze-dried product of levornidazole disodium phosphate for injection.

[0006] Compared with the prior art, the freeze-drying method of levornidazole phosphate disodium for injection provided by the present invention pre-freezes at a specific temperature, making the levornidazole phosphate disodium liquid medicine in a "supercooled" stage. The levornidazole phosphate disodium liquid medicine is gradually frozen to form freeze-dried crystals. The tiny crystals combine with each other to form irregular large granular crystals. Sublimation channels are formed between the large granular crystals, forming a larger and more uniform crystal form with a specific structure, increasing the sublimation drying channels of water during the subsequent sublimation drying process, being able to withstand better temperatures, and being beneficial to accelerating the sublimation rate during the subsequent sublimation drying process. In the pre-freezing stage of the present invention, the levornidazole phosphate disodium liquid medicine gradually changes from a liquid state to a homogeneous suspension-like material with solutes, and the solutes are not completely frozen; in the freezing stage, the suspension-like material is gradually frozen solid; in the sublimation drying stage, one-stage heating is used to remove the free water in the material, greatly shortening the freeze-drying time; finally, the bound water in the material is removed in the desorption stage.

[0007] The freeze-drying method of levornidazole phosphate disodium for injection provided by the present invention pre-freezes, freezes, sublimation dries, and desorption dries the levornidazole phosphate disodium liquid medicine at a specific temperature in sequence. The moisture in the material is gradually reduced, delaying the degradation rate of the freeze-dried product of levornidazole phosphate disodium for injection (abbreviated as freeze-dried product) during storage, and having lower moisture and impurity contents, better stability of the freeze-dried product, and higher drug safety, thereby improving the quality of the existing freeze-dried products.

[0008] Preferably, in S1, the levornidazole phosphate disodium liquid medicine comprises levornidazole phosphate disodium and water for injection with a mass ratio of 1:(17~22).

[0009] Preferably, in S1, the pH of the levornidazole phosphate disodium liquid medicine is 5~5.5.

[0010] The present invention uses a conventional pH regulator to adjust the pH of the levornidazole phosphate disodium liquid medicine within the above range.

[0011] Exemplarily, the levornidazole phosphate disodium liquid medicine can be filled, and the dose can be 2.5 mL / branch.

[0012] Preferably, in S1, it is cooled to -20°C~-15°C by means of programmed cooling, and the cooling rate is 0.8°C / min~1.2°C / min.

[0013] Preferably, in S1, the pre-freezing time is 50 min~70 min.

[0014] By defining the pre-freezing conditions, the present invention can ensure that the levornidazole phosphate disodium solution crystallizes sufficiently at a specific temperature, ensuring that the solute (injection water) in the resulting suspension is uniformly mixed and the solute is homogeneous, thereby facilitating the control of the crystal structure.

[0015] Preferably, in S1, it is cooled to -60°C to -40°C by a programmed cooling method, and the cooling rate is 0.8°C / min to 1.2°C / min.

[0016] Preferably, in S1, the freezing time is 100 min to 130 min.

[0017] By defining the freezing conditions, the present invention can ensure that the suspension with a specific structure formed in the pre-freezing stage is gradually frozen solid, which is beneficial to the subsequent operations.

[0018] Preferably, in S2, it is heated to -12°C to -8°C by a programmed heating method, and the heating time is 50 min to 70 min.

[0019] 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.

[0020] By controlling the sublimation drying conditions, the present invention can ensure that the free water in the material is removed only by a one-stage design, greatly shortening the time of the existing sublimation drying stage, improving the production efficiency, and saving the production cost.

[0021] Preferably, in S2, it is heated to 15°C to 25°C by a programmed heating method, and the heating rate is 0.8°C / min to 1.2°C / min.

[0022] Preferably, in S2, the vacuum degree of the desorption drying is 0.35 mbar to 0.45 mbar, and the desorption drying time is 2.5 h to 3.5 h.

[0023] By controlling the desorption drying conditions, the present invention can further ensure that the bound water in the material is effectively removed. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figures 1 to 2 It is the external view of the freeze-dried product of levornidazole phosphate disodium for injection in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0025] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] Example 1 This example provides a freeze-drying method for lyophilized sodium loxanamide phosphate for injection, which includes the following steps: Sa, Prepare the sodium loxanamide phosphate solution: Weigh 450 mL of water for injection into a beaker, add 25 g of the raw material sodium loxanamide phosphate, mix evenly, add a pH regulator to adjust the pH of the sodium loxanamide phosphate solution to 5.2, then make up the volume to 500 mL, fill it into vials at a filling volume of 2.5 mL / vial, and fill 200 vials to obtain the sodium loxanamide phosphate solution. Then, half-cork it and transfer it into a freeze dryer.

[0027] Sb, Cool the sodium loxanamide phosphate solution to -18 °C at a rate of 1 °C / min for pre-freezing and keep it warm for 60 min; then cool the resulting suspension to -50 °C at a rate of 1 °C / min for freezing and keep it warm for 120 min to obtain a frozen solid.

[0028] Sc, Raise the temperature of the frozen solid to -10 °C in 60 min for sublimation drying under a vacuum of 0.4 mbar and keep it warm for 10 h; then raise the temperature to 20 °C at a rate of 1 °C / min for desorption drying under a vacuum of 0.4 mbar and keep it warm for 3 h to obtain the lyophilized sodium loxanamide phosphate for injection.

[0029] The total time for the freeze-drying process from Sb to Sc is about 22 h, and the appearance of the obtained lyophilized sodium loxanamide phosphate for injection is a loose white block (see Figures 1 to 2 ).

[0030] Example 2 This example provides a freeze-drying method for lyophilized sodium loxanamide phosphate for injection, which includes the following steps: Sa, Prepare the sodium loxanamide phosphate solution: Weigh 450 mL of water for injection into a beaker, add 25 g of the raw material sodium loxanamide phosphate, mix evenly, add a pH regulator to adjust the pH of the sodium loxanamide phosphate solution to 5.5, then make up the volume to 500 mL, fill it into vials at a filling volume of 2.5 mL / vial, and fill 200 vials to obtain the sodium loxanamide phosphate solution. Then, half-cork it and transfer it into a freeze dryer.

[0031] Sb, Cool the sodium loxanamide phosphate solution to -20 °C at a rate of 0.8 °C / min for pre-freezing and keep it warm for 50 min; then cool the resulting suspension to -60 °C at a rate of 0.8 °C / min for freezing and keep it warm for 100 min to obtain a frozen solid.

[0032] Sc, Raise the temperature of the frozen solid to -12°C for sublimation drying at a rate of 0.45 mbar vacuum for 50 minutes, and keep the temperature for 9 hours; then raise the temperature to 15°C at a rate of 0.8°C / min for desorption drying at a rate of 0.45 mbar vacuum for 2.5 hours to obtain the freeze-dried product of levornidazole phosphate disodium for injection.

[0033] Calculated, the total time of the freeze-drying process from Sb to Sc is about 21 hours, and the appearance of the obtained freeze-dried product of levornidazole phosphate disodium for injection is a loose white block.

[0034] Example 3 This example provides a freeze-drying method for the freeze-dried product of levornidazole phosphate disodium for injection, including the following steps: Sa, Prepare the levornidazole phosphate disodium pharmaceutical solution: the same as Example 1, which will not be elaborated here.

[0035] Sb, Cool the levornidazole phosphate disodium pharmaceutical solution to -15°C at a rate of 1.2°C / min for pre-freezing and keep the temperature for 70 minutes; then cool the obtained suspension material to -40°C at a rate of 1.2°C / min for freezing and keep the temperature for 130 minutes to obtain a frozen solid.

[0036] Sc, Raise the temperature of the frozen solid to -8°C for sublimation drying at a rate of 0.35 mbar vacuum for 70 minutes, and keep the temperature for 11 hours; then raise the temperature to 25°C at a rate of 1.2°C / min for desorption drying at a rate of 0.35 mbar vacuum for 3.5 hours to obtain the freeze-dried product of levornidazole phosphate disodium for injection.

[0037] Calculated, the total time of the freeze-drying process from Sb to Sc is about 23 hours, and the appearance of the obtained freeze-dried product of levornidazole phosphate disodium for injection is a loose white block.

[0038] Comparative Example 1 This comparative example provides a freeze-drying method for the freeze-dried product of levornidazole phosphate disodium for injection, which is similar to Example 1, except that in Sb, the pre-freezing stage is omitted, and the levornidazole phosphate disodium pharmaceutical solution is directly frozen solid under freezing conditions. The specific steps are as follows: Sa, Prepare the levornidazole phosphate disodium pharmaceutical solution: the same as Example 1, which will not be elaborated here.

[0039] Sb, Cool the levornidazole phosphate disodium pharmaceutical solution to -40°C at a rate of 1.2°C / min for freezing and keep the temperature for 200 minutes to obtain a frozen solid.

[0040] Sc, The same as Example 1, which will not be elaborated here.

[0041] Comparative Example 2 This comparative example provides a freeze-drying method for the freeze-dried product of levornidazole phosphate disodium for injection, which is similar to Example 1, except that: in Sb, the pre-freezing temperature is -6°C. The remaining conditions are the same as those in Example 1 and will not be repeated.

[0042] Comparative Example 3 This comparative example provides a freeze-drying method for the freeze-dried product of levornidazole phosphate disodium for injection, which is similar to Example 1, except that: in Sb, the freezing temperature is -30°C. The remaining conditions are the same as those in Example 1 and will not be repeated.

[0043] Comparative Example 4 This comparative example provides a freeze-drying method for the freeze-dried product of levornidazole phosphate disodium for injection, which is similar to Example 1, except that: in Sc, the temperature of sublimation drying is 0°C. The remaining conditions are the same as those in Example 1 and will not be repeated.

[0044] The moisture and impurity tests were carried out on the freeze-dried products of Examples 1 to 3, Comparative Examples 1 to 4 of the present invention and the commercially available freeze-dried product of levornidazole phosphate disodium for injection. The specific results are shown in Table 1. The commercially available freeze-dried product of levornidazole phosphate disodium for injection was purchased from Jiangsu Zilong Pharmaceutical Co., Ltd., Yangzijiang Pharmaceutical Group, and the batch number was 23062051.

[0045] Table 1 Test results of examples, comparative examples and commercially available freeze-dried products

[0046] It can be seen from the test results of the examples of the present invention and the commercially available freeze-dried products that the appearance properties of the freeze-dried product of levornidazole phosphate disodium provided by the present invention are consistent with those of the commercially available freeze-dried products, both are loose white lumps, and the moisture and impurity contents are significantly less than those of the commercially available freeze-dried products. That is, the quality of the freeze-dried product of levornidazole phosphate disodium provided by the present invention is better. It can be seen from the test results of the freeze-dried products of levornidazole phosphate disodium in the examples and comparative examples of the present invention that after changing the conditions of pre-freezing, freezing or sublimation drying, the quality of the prepared freeze-dried product of levornidazole phosphate disodium has greatly decreased.

[0047] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A freeze-drying method for a freeze-dried product of levonidazole disodium phosphate for injection, characterized in that: The following steps are involved: S1, pre-freezing the levonidazole disodium phosphate solution at -20°C to -15°C, and then freezing the resulting suspension material at -60°C to -40°C to obtain a frozen solid; S2, sublimation drying the frozen solid at -12°C to -8°C, and then analytical drying at 15°C to 25°C to obtain a freeze-dried product of levornidazole disodium phosphate for injection.

2. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S1, the levonidazole disodium phosphate solution comprises levonidazole disodium phosphate and water for injection in a mass ratio of 1:(17-22); and / or In S1, the pH of the levornidazole disodium phosphate solution is 5-5.

5.

3. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S1, programmed cooling is used to reduce the temperature to -20℃~-15℃, and the cooling rate is 0.8℃ / min~1.2℃ / min.

4. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S1, the pre-freezing time is 50 min to 70 min.

5. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S1, programmed cooling is used to reduce the temperature to -60°C ~ -40°C, with a cooling rate of 0.8°C / min ~ 1.2°C / min.

6. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S1, the freezing time is 100 min to 130 min.

7. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S2, the temperature is raised to -12°C~-8°C by programmed heating, and the heating time is 50min~70min.

8. The freeze-drying method of the freeze-dried product of levornidazole disodium phosphate for injection according to claim 1, characterized in that: In S2, the vacuum degree of the sublimation drying is 0.35 mbar to 0.45 mbar, and the time of the sublimation drying is 9 h to 11 h.

9. The freeze-drying method of the freeze-dried product of levonidazole disodium phosphate for injection according to claim 1, characterized in that: In S2, the temperature is raised to 15°C~25°C by programmed heating, and the heating rate is 0.8°C / min~1.2°C / min.

10. The freeze-drying method of the freeze-dried product of levornidazole disodium phosphate for injection according to claim 1, characterized in that: 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.

Images