Preparation method of tedizolid phosphate for injection

Abstract

The invention discloses a preparation method of tedizolid phosphate for injection, and belongs to the field of pharmacy, the tedizolid phosphate for injection comprises tedizolid phosphate, mannitol, sodium hydroxide and water for injection, and the preparation method mainly controls material components and component proportions, and mutual combination of a raw material dissolving mode and a freeze-drying mode in a material liquid preparation process. Finally, by means of the preparation method, the raw material tedizolid phosphate in the production process can be fully and rapidly dissolved, and the produced tedizolid phosphate medicine for injection is high in mass content, low in related substance content and good in quality stability.

Description

Technical Field

[0001] The invention relates to a method for preparing a medicine, in particular to a method for preparing tedizolid phosphate for injection, and belongs to the field of pharmaceuticals. Background Art

[0002] Tedizolid phosphate is a second-generation oxazolidinone antibiotic with a different mechanism of action from ordinary antibacterial drugs. It achieves antibacterial effects by binding to the 50S subunit of bacterial ribosomes and interfering with the synthesis of bacterial proteins. Therefore, it is not easy to produce cross-resistance with other types of antibiotics, and has the advantage of low natural resistance frequency. It is suitable for acute bacterial skin and skin structure infections caused by Gram-positive sensitive strains such as Staphylococcus aureus (including methicillin-resistant and methicillin-sensitive strains), Streptococcus pyogenes, Streptococcus lactis, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus asteri), Enterococcus faecalis, etc.

[0003] Tedizolid phosphate for injection is produced by the preparation method of aseptic process preparation of raw material tedizolid phosphate and its excipients. The finished product tedizolid phosphate for injection is a white or off-white loose block or powder. Tedizolid phosphate for injection is used for acute bacterial skin and skin structure infections in adults caused by specific sensitive bacteria. At present, in the preparation and production process of tedizolid phosphate for injection, the raw material tedizolid phosphate is difficult to dissolve, which may lead to low quality content of the produced drug and poor drug quality stability. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing tedizolid phosphate for injection, so as to solve the problem that the raw material tedizolid phosphate is difficult to dissolve in the production process of the prior art, resulting in low drug quality content.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0006] A method for preparing tedizolid phosphate for injection, wherein the composition of tedizolid phosphate for injection includes: tedizolid phosphate, mannitol, sodium hydroxide, and water for injection; the method for preparing tedizolid phosphate for injection includes the following steps:

[0007] S1. Weighing: Weigh the amount of tedizolid phosphate, mannitol, sodium hydroxide, and water for injection according to the prescription amount and set aside;

[0008] S2. Preparation of feed liquid:

[0009] S21. Prepare 2 mol / L sodium hydroxide solution for standby use;

[0010] S22. Add 50% of the prescribed amount of water for injection to the batching tank, turn on the stirring mode, set the stirring speed, wait for the water temperature to cool to below 40°C, add the prescribed amount of mannitol, stir for 10-15 minutes, and dissolve the mannitol;

[0011] S23. Under stirring, slowly add the prescribed amount of tedizolid phosphate, set the stirring speed, and stir for 8-10min to disperse the raw material tedizolid phosphate;

[0012] S24. Slowly add 2 mol / L sodium hydroxide solution three times and stir to completely dissolve the raw material;

[0013] S25. Adjust the pH value of the solution: slowly add 2 mol / L sodium hydroxide solution in small amounts and multiple times, stirring for 5-8 minutes each time;

[0014] S26. Add water for injection to the full amount, stir evenly, and control the temperature of the liquid medicine to less than 30°C;

[0015] S27. The liquid medicine is filtered through the filter element and then circulated into the batching tank until the liquid medicine intermediate is tested and qualified;

[0016] S3. Filling and semi-pressing: Fill the prepared liquid medicine, and perform semi-pressing after filling;

[0017] S4. Freeze drying: freeze-dry the half-filled vials in three stages, namely pre-freezing, primary drying, and secondary drying. After freeze drying, fully stopper and cap are performed to obtain tedizolid phosphate for injection.

[0018] Furthermore, the weight ratio of tedizolid phosphate to mannitol is 2:1; and the amount of sodium hydroxide is 34%-37% of the weight of mannitol.

[0019] Further, in steps S22 and S23, the stirring speed is 40-50 Hz.

[0020] Further, in step S24, for the first time, 60%-80% of the prepared amount of 2mol / L sodium hydroxide solution is slowly added through a peristaltic pump, and stirred for 10-15 minutes using a silicone tube; for the second time, 10%-20% of the prepared amount of 2mol / L sodium hydroxide solution is slowly added through a peristaltic pump, and stirred for 10-15 minutes; for the third time, 10%-20% of the prepared amount of 2mol / L sodium hydroxide solution is slowly added through a peristaltic pump, and the internal circulation is started after the addition is completed, and the circulation stirring is continued for 20-25 minutes to completely dissolve the raw materials.

[0021] Further, in step S24, the peristaltic pump rate is 250 ml / min-500 ml / min.

[0022] Further, in step S25, the pH value is adjusted to 7.6-7.8.

[0023] Further, in step S27, the intermediate detection includes: properties, pH value, density, microbial load, bacterial endotoxin, and intermediate content.

[0024] Further, in step S4, pre-freeze: lower the partition temperature to -40±2°C and maintain it for 4 hours after reaching the temperature.

[0025] Further, in step S4, primary drying is performed: the vacuum degree is set to 15 Pa, the partition temperature is raised to -15±2°C in 3 hours, and maintained for 4 hours after the ice crystals disappear.

[0026] Further, in step S4, secondary drying is performed: the partition temperature is raised to 0°C in 2 hours and maintained for 1 hour; the partition temperature is raised to 40±5°C in 5 hours and maintained for 20 hours, and the aeration is turned off and maintained for another 5 hours.

[0027] Due to the adoption of the above technical solution, the technical progress achieved by the present invention is:

[0028] The preparation method of the present invention enables the raw material tedizolid phosphate in the production process to be fully and quickly dissolved, and the produced tedizolid phosphate for injection has a high drug quality content, a low content of related substances and good drug quality stability.

[0029] First, the present invention adopts relatively simple material combination in the prescription of material components and component ratio, reduces the related substances produced in the process of carrying or each auxiliary material dissolving mutually in the source, controls the generation of related substances, and then produces a relatively stable feed liquid system by the interaction between each component ratio. Secondly, in the raw material dissolution method of the preparation process, 2mol / L sodium hydroxide solution is added in batches to promote the dissolution of raw material tedizolid phosphate, and the acid-base property of the solution is slowly changed during the dissolution process, so that the raw material is more fully and completely dissolved, and the balanced solution environment can well control the generation of related substances, so that the related substances are relatively low, and the raw material can be fully and thoroughly dissolved, so the liquid content is relatively high. Finally, the freeze-drying method of pre-freezing, primary drying, secondary drying temperature and time combined in the freeze-drying process, so that the moisture of the freeze-dried finished product can be well volatilized, so that the moisture is controlled within a relatively low range, so the related substances in the medicine are also curbed, and the content is also guaranteed, and the stability of the drug quality is improved as a whole. DETAILED DESCRIPTION

[0030] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] The present invention is further described in detail below in conjunction with embodiments:

[0032] A preparation method of tedizolid phosphate for injection, comprising: tedizolid phosphate, mannitol, sodium hydroxide, and water for injection; wherein the weight ratio of tedizolid phosphate to mannitol is 2:1, the amount of sodium hydroxide is 34%-37% of the weight of mannitol, the volume of a single vial is 2 ml, and the water for injection is added to 2 ml. The water for injection will be volatilized and removed during the preparation process.

[0033] Single dose (specification 200mg):

[0034] Tedizolid phosphate: 200 mg;

[0035] Mannitol: 100 mg;

[0036] Sodium hydroxide: 34mg-37mg;

[0037] Add water for injection to 2 ml.

[0038] The preparation method of tedizolid phosphate for injection comprises the following steps:

[0039] S1. Weighing: Weigh the amount of tedizolid phosphate, mannitol, sodium hydroxide, and water for injection according to the prescription amount and set aside;

[0040] S2. Preparation of liquid feed:

[0041] S21.2 mol / L sodium hydroxide solution preparation: weigh sodium hydroxide, add injection water, stir to dissolve and make up to volume, stir evenly, and place at room temperature for use. In addition, when used to adjust the pH value, it can be prepared again according to the dosage requirements.

[0042] S22. Add 50% of the prescribed amount of water for injection into the batching tank, start stirring, set the stirring speed to 40-50 Hz, wait until the water temperature cools to below 40°C, add the prescribed amount of mannitol, and stir for 10-15 minutes to dissolve the mannitol.

[0043] S23. While stirring, slowly add the prescribed amount of tedizolid phosphate, set the stirring speed to 40-50 Hz, and stir for 8-10 minutes to disperse the raw material tedizolid phosphate.

[0044] S24. Slowly add 2mol / L sodium hydroxide solution three times and stir to completely dissolve the raw materials; specifically: for the first time, slowly add 60%-80% of the prepared amount (the prepared amount refers to the amount of solution prepared by the sodium hydroxide prescription amount, the same below) of 2mol / L sodium hydroxide through a peristaltic pump, the peristaltic pump rate is 250ml / min-500ml / min, and use 1 silicone tube to stir for 10-15min; for the second time, slowly add 10%-20% of the prepared amount of 2mol / L sodium hydroxide solution through a peristaltic pump, the peristaltic pump rate is 250ml / min-500ml / min, and stir for 10-15min; for the third time, slowly add 10%-20% of the prepared amount of 2mol / L sodium hydroxide solution through a peristaltic pump, the peristaltic pump rate is 250ml / min-500ml / min, start the internal circulation after adding, and continue to circulate and stir for 20-25min to completely dissolve the raw materials.

[0045] S25. Adjust the pH value of the solution: slowly add 2 mol / L sodium hydroxide solution in small amounts and multiple times, stirring for 5-8 minutes each time, and adjust the pH value to 7.6-7.8.

[0046] S26. Add water for injection to the full amount, stir for 20-25 minutes, open the jacket refrigerant, and control the temperature of the drug solution to less than 30°C.

[0047] S27. The drug solution is filtered through a 0.45μm PES filter element and then recycled into the batching tank. Samples are taken from the sampling port of the batching tank for intermediate testing: properties, pH value, content, bacterial endotoxins, density, and microbial load. If the test is qualified, proceed to the next step.

[0048] S3. Filling and semi-cording: Fill the prepared liquid medicine, and check the filling volume during the filling process. The filling volume difference is controlled within the range of ±3%, and the filled medicine bottle is semi-corked.

[0049] S4. Lyophilization:

[0050] The freeze-drying operation of the filled and half-corked vials is carried out in three stages, namely:

[0051] S41. Pre-freezing: Lower the shelf temperature to -40±2℃ and maintain it for 4 hours.

[0052] S42. Primary drying: Set the vacuum degree to 15Pa, raise the temperature of the partition to -15±2℃ in 3 hours, and maintain it for 4 hours after the ice crystals disappear.

[0053] S43. Secondary drying: raise the temperature of the partition to 0°C in 2 hours and keep it for 1 hour; raise the temperature of the partition to 40±5°C in 5 hours and keep it for 20 hours, turn off the aeration and continue to keep it for 5 hours.

[0054] S44. After the back pressure test (≤5.0pa / 5min) is passed, fill with nitrogen to negative pressure, the negative pressure control range is: -0.01 to -0.02MPa, perform full pressure plugging, and then roll capping to obtain tedizolid phosphate for injection.

[0055] Example 1

[0056] A method for preparing tedizolid phosphate for injection, comprising: tedizolid phosphate, mannitol, sodium hydroxide, and water for injection; the batch quantity of tedizolid phosphate for injection produced in this embodiment 1 is 2000 vials. 2500 vials Prescription quantity:

[0057] Tedizolid phosphate: 500g;

[0058] Mannitol: 250g;

[0059] Sodium hydroxide: 88g;

[0060] Add water for injection to 5L.

[0061] The preparation method comprises the following steps:

[0062] S1. Weighing: Weigh the amount of tedizolid phosphate, mannitol, sodium hydroxide, and water for injection according to the prescription amount and set aside;

[0063] S2. Preparation of liquid feed:

[0064] S2 Preparation of 1.2 mol / L sodium hydroxide solution: Weigh 88 g of sodium hydroxide, add water for injection, stir to dissolve and make up to 1.1 L, stir evenly, and let it stand at room temperature for use.

[0065] S22. Add 2.5 L of water for injection into the batching tank, start stirring, set the stirring speed to 45 Hz, wait until the water temperature cools down to below 40°C, add the prescribed amount of mannitol, and stir for 10 minutes to dissolve the mannitol.

[0066] S23. While stirring, slowly add the prescribed amount of tedizolid phosphate, set the stirring speed to 45 Hz, and stir for 10 minutes to disperse the raw material tedizolid phosphate.

[0067] S24. Slowly add 2mol / L sodium hydroxide solution three times, stirring to completely dissolve the raw materials; specifically: the first time, slowly add 800ml of 2mol / L sodium hydroxide by a peristaltic pump at a rate of 400ml / min, and use a silicone tube to stir for 13min; the second time, slowly add 150ml of 2mol / L sodium hydroxide solution by a peristaltic pump at a rate of 400ml / min, and stir for 13min; the third time, slowly add 150ml of 2mol / L sodium hydroxide solution by a peristaltic pump at a rate of 400ml / min, start the internal circulation after adding, and continue to circulate and stir for 22min to completely dissolve the raw materials.

[0068] S25. Adjust the pH value of the solution: slowly add 2 mol / L sodium hydroxide solution in small amounts and multiple times, stirring for 5 minutes each time, and adjust the pH value to 7.8.

[0069] S26. Add water for injection to a total of 5 L, stir for 20 min, open the jacket refrigerant, and control the liquid temperature to 22 °C.

[0070] S27. The drug solution is filtered through a 0.45μm PES filter element and then recycled into the batching tank. Samples are taken at the sampling port of the batching tank for intermediate testing: properties, pH value, content, bacterial endotoxins, density, and microbial load.

[0071] S3. Filling and semi-cording: Fill the prepared liquid medicine, and check the filling volume during the filling process. The filling volume difference is controlled within the range of ±3%, and the filled medicine bottle is semi-corked.

[0072] S4. Lyophilization:

[0073] The freeze-drying operation of the filled and half-corked vials is carried out in three stages, namely:

[0074] S41. Pre-freeze: reduce the shelf temperature to -40°C and maintain it for 4 hours.

[0075] S42. Primary drying: Set the vacuum degree to 15Pa, raise the temperature of the partition to -15°C over 3 hours, and maintain it for 4 hours after the ice crystals disappear.

[0076] S43. Secondary drying: raise the partition temperature to 0°C in 2 hours and maintain it for 1 hour; raise the partition temperature to 40°C in 5 hours and maintain it for 20 hours, turn off the aeration, and continue to maintain it for 5 hours.

[0077] S44. After the back pressure test (≤5.0pa / 5min) is passed, fill with nitrogen to negative pressure, the negative pressure control range is: -0.01 to -0.02MPa, perform full pressure plugging, and then roll capping to obtain tedizolid phosphate for injection.

[0078] Example 2

[0079] A method for preparing tedizolid phosphate for injection, comprising: tedizolid phosphate, mannitol, sodium hydroxide, and water for injection; the batch quantity of tedizolid phosphate for injection produced in Example 2 is 1000 vials. Prescription quantity for 1000 vials:

[0080] Tedizolid phosphate: 200g;

[0081] Mannitol: 100g;

[0082] Sodium hydroxide: 34 g;

[0083] Add water for injection to 2L.

[0084] The preparation method comprises the following steps:

[0085] S1. Weighing: Weigh the amount of tedizolid phosphate, mannitol, sodium hydroxide, and water for injection according to the prescription amount and set aside;

[0086] S2. Preparation of liquid feed:

[0087] S2 Preparation of 1.2 mol / L sodium hydroxide solution: Weigh 34 g of sodium hydroxide, add water for injection, stir to dissolve and make up to 425 ml, stir evenly, and place at room temperature for use.

[0088] S22. Add 1L of water for injection into the batching tank, start stirring, set the stirring speed to 40Hz, wait until the water temperature cools down to below 40°C, add the prescribed amount of mannitol, and stir for 15 minutes to dissolve the mannitol.

[0089] S23. While stirring, slowly add the prescribed amount of tedizolid phosphate, set the stirring speed to 40 Hz, and stir for 9 minutes to disperse the raw material tedizolid phosphate.

[0090] S24. Slowly add 2mol / L sodium hydroxide solution three times, stirring to completely dissolve the raw materials; specifically: the first time, slowly add 255ml of 2mol / L sodium hydroxide by a peristaltic pump at a rate of 250ml / min, and use a silicone tube to stir for 10min; the second time, slowly add 85ml of 2mol / L sodium hydroxide solution by a peristaltic pump at a rate of 250ml / min, and stir for 10min; the third time, slowly add 85ml of 2mol / L sodium hydroxide solution by a peristaltic pump at a rate of 250ml / min, and start the internal circulation after adding, and continue to circulate and stir for 20min to completely dissolve the raw materials.

[0091] S25. Adjust the pH value of the solution: slowly add 2 mol / L sodium hydroxide solution in small amounts and multiple times, stirring for 8 minutes each time, and adjust the pH value to 7.7.

[0092] S26. Add water for injection to a total of 2 L, stir for 22 min, open the jacket refrigerant, and control the liquid temperature to 25 °C.

[0093] S27. The drug solution is filtered through a 0.45μm PES filter element and then recycled into the batching tank. Samples are taken at the sampling port of the batching tank for intermediate testing: properties, pH value, content, bacterial endotoxins, density, and microbial load.

[0094] S3. Filling and semi-cording: Fill the prepared liquid medicine, and check the filling volume during the filling process. The filling volume difference is controlled within the range of ±3%, and the filled medicine bottle is semi-corked.

[0095] S4. Lyophilization:

[0096] The freeze-drying operation of the filled and half-corked vials is carried out in three stages, namely:

[0097] S41. Pre-freezing: Lower the shelf temperature to -38°C and maintain it for 5 hours.

[0098] S42. Primary drying: Set the vacuum degree to 15 Pa, raise the partition temperature to -13°C over 3 hours, and maintain it for 5 hours after the ice crystals disappear.

[0099] S43. Secondary drying: raise the partition temperature to 0°C in 2 hours and maintain it for 1 hour; raise the partition temperature to 45°C in 5 hours and maintain it for 20 hours, turn off the aeration and continue to maintain it for 5 hours.

[0100] S44. After the back pressure test (≤5.0pa / 5min) is passed, fill with nitrogen to negative pressure, the negative pressure control range is: -0.01 to -0.02MPa, perform full pressure plugging, and then roll capping to obtain tedizolid phosphate for injection.

[0101] Example 3

[0102] A method for preparing tedizolid phosphate for injection, comprising: tedizolid phosphate, mannitol, sodium hydroxide, and water for injection; the batch quantity of tedizolid phosphate for injection produced in this embodiment 3 is 3000 vials. 3000 vials prescription quantity:

[0103] Tedizolid phosphate: 600g;

[0104] Mannitol: 300g;

[0105] Sodium hydroxide: 102g;

[0106] Add water for injection to 6L.

[0107] The preparation method comprises the following steps:

[0108] S1. Weighing: Weigh the amount of tedizolid phosphate, mannitol, sodium hydroxide, and water for injection according to the prescription amount and set aside;

[0109] S2. Preparation of liquid feed:

[0110] S2 Preparation of 1.2 mol / L sodium hydroxide solution: Weigh 102 g of sodium hydroxide, add water for injection, stir to dissolve and make up to 1275 ml, stir evenly, and place at room temperature for use.

[0111] S22. Add 3 L of water for injection into the batching tank, start stirring, set the stirring speed to 50 Hz, wait until the water temperature cools to below 40°C, add the prescribed amount of mannitol, and stir for 10 minutes to dissolve the mannitol.

[0112] S23. While stirring, slowly add the prescribed amount of tedizolid phosphate, set the stirring speed to 50 Hz, and stir for 8 minutes to disperse the raw material tedizolid phosphate.

[0113] S24. Slowly add 2mol / L sodium hydroxide solution three times, stirring to completely dissolve the raw materials; specifically: the first time, slowly add 765ml of 2mol / L sodium hydroxide by a peristaltic pump at a rate of 500ml / min, and use a silicone tube to stir for 15min; the second time, slowly add 255ml of 2mol / L sodium hydroxide solution by a peristaltic pump at a rate of 500ml / min, and stir for 15min; the third time, slowly add 255ml of 2mol / L sodium hydroxide solution by a peristaltic pump at a rate of 500ml / min, start the internal circulation after adding, and continue to circulate and stir for 25min to completely dissolve the raw materials.

[0114] S25. Adjust the pH value of the solution: slowly add 2 mol / L sodium hydroxide solution in small amounts and multiple times, stirring for 8 minutes each time, and adjust the pH value to 7.8.

[0115] S26. Add water for injection to a total of 6 L, stir for 25 min, open the jacket refrigerant, and control the temperature of the drug solution to 20°C.

[0116] S27. The drug solution is filtered through a 0.45μm PES filter element and then recycled into the batching tank. Samples are taken at the sampling port of the batching tank for intermediate testing: properties, pH value, content, bacterial endotoxins, density, and microbial load.

[0117] S3. Filling and semi-cording: Fill the prepared liquid medicine, and check the filling volume during the filling process. The filling volume difference is controlled within the range of ±3%, and the filled medicine bottle is semi-corked.

[0118] S4. Lyophilization:

[0119] The freeze-drying operation of the filled and half-corked vials is carried out in three stages, namely:

[0120] S41. Pre-freeze: reduce the shelf temperature to -42°C and maintain it for 4 hours.

[0121] S42. Primary drying: Set the vacuum degree to 15 Pa, raise the temperature of the partition to -17°C over 3 hours, and maintain it for 4 hours after the ice crystals disappear.

[0122] S43. Secondary drying: raise the partition temperature to 0°C in 2 hours and maintain it for 1 hour; raise the partition temperature to 35°C in 5 hours and maintain it for 20 hours, turn off the aeration and continue to maintain it for 5 hours.

[0123] S44. After the back pressure test (≤5.0pa / 5min) is passed, fill with nitrogen to negative pressure, the negative pressure control range is: -0.01 to -0.02MPa, perform full pressure plugging, and then roll capping to obtain tedizolid phosphate for injection.

[0124] The above is the production and preparation process of Example 1, Example 2, and Example 3, wherein the prescription dosage of Example 1, Example 2, and Example 3 is shown in the following table:

[0125] Table 1: Summary of prescription quantities of Examples 1-3

[0126] project Example 1 Example 2 Example 3 Batch size 2500 1000 pieces 3000 pieces Tedizolid phosphate 500g 200g 600g Mannitol 250g 100g 300g Sodium hydroxide 88g 34g 102g Water for injection Add to 5L Add to 2L Add up to 6L

[0127] Quality evaluation standard of Tedizolid Phosphate for Injection intermediates:

[0128] (1) Properties: Colorless, clear liquid;

[0129] (2) pH value: should be 7.5-7.9;

[0130] (3) Density: should be 1.04g / ml-1.10g / ml;

[0131] (4) Bacterial endotoxin: The amount of endotoxin in 1 mg of tedizolid phosphate should be less than 0.35 EU;

[0132] (5) Intermediate content: 95.0 mg / ml-105.0 mg / ml.

[0133] The drug solution prepared by circulating filtration through a 0.45 μm PES filter cartridge in Example 1-3 was tested for intermediates. The results are shown in the following table:

[0134] Table 2: Quality test results of the intermediates of Examples 1-3

[0135] project Example 1 Example 2 Example 3 Characteristics Colorless clear liquid Colorless clear liquid Colorless clear liquid pH 7.8 7.7 7.8 density 1.0630g / ml 1.0645g / ml 1.0609g / ml Bacterial endotoxins Comply with regulations Comply with regulations Comply with regulations Intermediate content 101.4mg / ml 99.9mg / ml 98.7mg / ml

[0136] The quality test results of the intermediates of the drug solutions in Examples 1-3 all meet the requirements and are within the qualified range. Therefore, the quality of the drug solutions prepared in Examples 1-3 is good, the quality of the drug solutions is well controlled during the preparation stage, the content of bacterial endotoxins and intermediates is well controlled, the bacterial endotoxins meet the requirements, and the content of intermediates is high, ensuring that the subsequent drugs have a high quality content.

[0137] Quality evaluation standards for Tedizolid Phosphate for Injection:

[0138] (1) Appearance: White or off-white mass or powder;

[0139] (2) Alkalinity: 7.4-8.1;

[0140] (3) Solution clarity and color: The solution should be clear and colorless. If turbid, it should not be thicker than the No. 2 turbidity standard. If colored, it should not be darker than the No. 1 yellow standard colorimetric solution.

[0141] (4) Related substances: Impurity A ≤ 0.3%; Impurity B ≤ 0.6%; Impurity C ≤ 0.5%; Impurity D ≤ 0.3%; Impurity E ≤ 0.5%; Impurity F ≤ 0.3%; Impurity G ≤ 1.0%; Other individual impurities ≤ 0.2%; Total amount of impurities ≤ 2.0%;

[0142] (5) Moisture content: not more than 3.0%;

[0143] (6) Bacterial endotoxin: The amount of endotoxin in 1 mg of tedizolid phosphate should be less than 0.35 EU;

[0144] (7) Visible foreign matter: The visible foreign matter inspection method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0904) should comply with the regulations.

[0145] (8) Insoluble particles: Each test sample container shall contain no more than 3,000 particles of 10 μm or larger, and no more than 300 particles of 25 μm or larger;

[0146] (9) Content: Contains tedizolid phosphate (C 17 H 16 FN 6 O 6 P) should be 90.0%-110.0% of the labeled amount.

[0147] The tedizolid phosphate for injection prepared in Example 1-3 was tested for drug quality, and the results are shown in the following table:

[0148] Table 3: Results of drug quality testing in Examples 1-3

[0149]

[0150] The drug quality test results of Examples 1-3 all meet the requirements and are within the qualified range. Therefore, the tedizolid phosphate for injection prepared in Examples 1-3 has high drug quality and good quality.

[0151] Drug stability study: The tedizolid phosphate for injection prepared in Example 1-3 was subjected to a 6-month accelerated stability study. The accelerated test conditions were: temperature 40°C ± 2°C, humidity 75% ± 5%. The properties, alkalinity, solution clarity and color, related substances, water content, bacterial endotoxins, visible foreign matter, insoluble particles, and content were tested and the changes were observed. The results are shown in the following table:

[0152] Table 4: Accelerated stability test results of Example 1

[0153]

[0154] Note: “N / A” means not tested, the same below.

[0155] Table 5: Accelerated stability test results of Example 2

[0156]

[0157]

[0158] Table 6: Accelerated stability test results of Example 3

[0159]

[0160] From the results of the 6-month accelerated stability study, the drug quality stability obtained by the preparation method of Examples 1-3 is good, and the content and related substances change steadily during the accelerated stability study period. Therefore, it can be seen from the results of the accelerated stability study that the entire process preparation process of the embodiment of the present invention (including the prescription process, the preparation process, the production operation control and the aseptic process) has good operability and can obtain drugs with stable quality. Specifically, by limiting the combination of the prescription process, the preparation process, the production operation control and the aseptic process, the quality content and related substances of the drug are controlled, and a drug with good quality content stability and low related substances is obtained.

[0161] The advantages of the present invention are mainly as follows: (1) A relatively simple material combination is used in the prescription of material components and component ratios, which reduces a large number of auxiliary materials and related substances produced during the process of carrying auxiliary materials or mixing with each other, thereby controlling the generation of related substances at the source; and then a relatively stable liquid system is produced through the interaction between the proportions of each component, thereby ensuring the next step of drug production. (2) In the raw material dissolution method of the preparation process, 2 mol / L sodium hydroxide solution is added in batches to promote the dissolution of the raw material tedizolid phosphate, and the acid-base properties of the solution are slowly changed during the dissolution process, so that the raw material is more fully and completely dissolved, and the balanced solution environment can well control the generation of related substances, so that the related substances are relatively low and fully and thoroughly dissolved, so the drug liquid content is relatively high. (3) The freeze-drying method of pre-freezing, primary drying, and secondary drying temperature and time combined in the freeze-drying process enables the moisture of the freeze-dried product to volatilize well, thereby controlling the moisture within a relatively low range, so that the related substances in the drug are also contained, the content is also guaranteed, and the stability of the drug quality is improved.

[0162] Comparative Example 1

[0163] As a comparative experiment of Example 1, the difference is that the dissolution method of the raw material in step S24 is different, and the rest of the operations are the same as those of Example 1. Specifically, in Comparative Example 1, the 2 mol / L sodium hydroxide solution is not added in batches, but the entire configuration amount of 1.1 L of 2 mol / L sodium hydroxide solution is directly added to the liquid at one time for stirring to dissolve the raw material tedizolid phosphate.

[0164] Comparative Example 2

[0165] As a comparative experiment of Example 1, the difference is that the freeze-drying process of step S4 is different, and the rest of the operations are the same as Example 1. Specifically, the freeze-drying process of Comparative Example 2 is as follows: (1) pre-freezing: the temperature of the drug solution is reduced to -30°C, the cooling time is 30 minutes, and the duration is 3 hours; (2) primary drying: heating to -25°C, the heating time is 120 minutes, and the duration is 3 hours; (3) secondary drying: continue to heat to 30°C, the heating time is 12 minutes, and the duration is 4 hours; continue to heat to 60°C, the heating time is 60 minutes, and the duration is 3 hours.

[0166] The tedizolid phosphate for injection prepared in Comparative Example 1-2 was tested for drug quality, and the results are shown in the following table:

[0167] Table 7: Comparative Example 1-2 Drug Quality Test Results

[0168]

[0169] Comparison of the drug quality test results of Comparative Example 1 and Example 1 shows that the related substances of Comparative Example 1 are relatively high, among which other single impurities (unknown impurities) are significantly increased, and the content is relatively low, and the moisture remains unchanged. Mainly due to the different raw material dissolution methods in the preparation process of Comparative Example 1, the method of directly adding 2 mol / L sodium hydroxide solution all at once causes the acid-base properties of the solution in which the raw material liquid is located to change suddenly, and the raw material may produce related impurities during the dissolution process, including known impurities and unknown impurities, so the related substances are relatively high, especially other single impurities (unknown impurities) are significantly increased, resulting in a relatively poor dissolution effect of the raw material, so the content is relatively low, which affects the quality of the drug as a whole.

[0170] In the preparation process of Example 1, a method of adding 2 mol / L sodium hydroxide solution in batches to promote the dissolution of the raw material tedizolid phosphate is adopted. During the dissolution process, the acid-base properties of the solution are slowly changed, so that the raw material is more fully and completely dissolved. During the dissolution process, the production of related substances can be well controlled, so that the related substances are relatively low and fully and thoroughly dissolved. Therefore, the content of the drug solution is relatively high, which ensures the high quality of the drug production process.

[0171] Comparison of the drug quality test results of Comparative Example 2 and Example 1 shows that the moisture content of Comparative Example 2 is relatively high, and the related substances are also relatively high and the content is low. This is mainly due to the different freeze-drying methods in the freeze-drying process of Comparative Example 2, including the combination of the temperature and time of pre-freezing, primary drying, and secondary drying, so that the moisture of the freeze-dried product cannot be well volatilized, so the moisture content is high. Drugs with higher moisture content may cause the production of related substances, so the related substances are also relatively high, and may also cause the content to degrade, so the content is relatively low, thereby affecting the quality of the drug as a whole.

[0172] The freeze-drying method of Example 1, which combines pre-freezing, primary drying, and secondary drying temperature and time, enables the moisture of the freeze-dried product to volatilize well, thereby controlling the moisture within a lower range. Therefore, the related substances in the medicine are also contained and the content is guaranteed, thereby improving the stability of the quality of the medicine as a whole.

[0173] Drug stability study: The tedizolid phosphate for injection prepared in Comparative Example 1-2 was subjected to a 6-month accelerated stability study. The accelerated test conditions were: temperature 40°C ± 2°C, humidity 75% ± 5%. The properties, alkalinity, solution clarity and color, related substances, moisture, bacterial endotoxins, visible foreign matter, insoluble particles, and content were tested and the changes were observed. The results are shown in the following table:

[0174] Table 8: Comparative Example 1 Accelerated Stability Test Results

[0175]

[0176]

[0177] Table 9: Comparative Example 2 Accelerated Stability Test Results

[0178]

[0179] The results of the accelerated stability investigation of Comparative Example 1, Comparative Example 2 and Example 1 show that, regardless of whether the drug produced by the method of Comparative Example 1 or Comparative Example 2 shows a relatively obvious instability phenomenon during the accelerated stability investigation, that is, the related substances and water content of the drug show an obvious increasing trend, and the content is obviously degraded, showing a downward trend. However, the method of Example 1 combines the control of the dissolution process of the raw materials and the control parameters of freeze-drying to produce a drug with good quality stability. During the accelerated stability investigation, the related substances, water content of the drug are relatively stable, and basically no large fluctuations occur, all within a controllable range. Therefore, the drug quality stability prepared by the method of the present invention is good.

[0180] In summary, this embodiment confirms that the tedizolid phosphate for injection produced by the preparation method of the present invention is mainly achieved by controlling the material components and component ratios, the raw material dissolution method in the preparation process, and the combination of the freeze-drying method, so that the raw material tedizolid phosphate can be fully, quickly and completely dissolved, and the final obtained drug quality content is high, the related substances are low, and the drug quality stability is good. The problem of low drug quality content caused by the difficulty in dissolving the raw material tedizolid phosphate in the production process of the prior art is solved, and the problem of poor drug quality stability is also solved.

[0181] The embodiments described above are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. Such modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention, and all of them belong to the protection scope of the present invention.

Claims

1. A method for preparing tedizolid phosphate for injection, characterized in that: The composition of tedizolid phosphate for injection includes: tedizolid phosphate, mannitol, sodium hydroxide, and water for injection; the preparation method of tedizolid phosphate for injection includes the following steps: S1. Weighing: Weigh the amount of tedizolid phosphate, mannitol, sodium hydroxide, and water for injection according to the prescription amount and set aside; S2. Preparation of liquid feed: S21. Prepare 2 mol / L sodium hydroxide solution for standby use; S22. Add 50% of the prescribed amount of water for injection to the batching tank, turn on the stirring mode, set the stirring speed, wait for the water temperature to cool to below 40°C, add the prescribed amount of mannitol, stir for 10-15 minutes, and dissolve the mannitol; S23. Under stirring, slowly add the prescribed amount of tedizolid phosphate, set the stirring speed, and stir for 8-10min to disperse the raw material tedizolid phosphate; S24. Slowly add 2 mol / L sodium hydroxide solution three times and stir to completely dissolve the raw material; S25. Adjust the pH value of the solution: slowly add 2 mol / L sodium hydroxide solution in small amounts and multiple times, stirring for 5-8 minutes each time; S26. Add water for injection to the full amount, stir evenly, and control the temperature of the liquid medicine to less than 30°C; S27. The liquid medicine is filtered through the filter element and then circulated into the batching tank until the liquid medicine intermediate is tested and qualified; S3. Filling and semi-pressing: Fill the prepared liquid medicine, and perform semi-pressing after filling; S4. Freeze drying: freeze-dry the half-filled vials in three stages, namely pre-freezing, primary drying, and secondary drying. After freeze drying, fully stopper and cap are performed to obtain tedizolid phosphate for injection.

2. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: The weight ratio of tedizolid phosphate to mannitol is 2:1; the amount of sodium hydroxide is 34%-37% of the weight of mannitol.

3. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In steps S22 and S23, the stirring speed is 40-50 Hz.

4. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In step S24, for the first time, 60%-80% of the prepared 2 mol / L sodium hydroxide solution is slowly added by a peristaltic pump, and stirred for 10-15 minutes using a silicone tube; The second time, 10%-20% of the prepared amount of 2mol / L sodium hydroxide solution is slowly added through a peristaltic pump and stirred for 10-15min; the third time, 10%-20% of the prepared amount of 2mol / L sodium hydroxide solution is slowly added through a peristaltic pump, and the internal circulation is started after the addition, and the circulation stirring is continued for 20-25min to completely dissolve the raw materials.

5. The method for preparing tedizolid phosphate for injection according to claim 4, characterized in that: In step S24, the peristaltic pump rate is 250 ml / min-500 ml / min.

6. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In step S25, the pH value is adjusted to 7.6-7.

8.

7. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In step S27, intermediate detection includes: properties, pH value, density, microbial load, bacterial endotoxin, and intermediate content.

8. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In step S4, pre-freeze: lower the shelf temperature to -40±2°C and maintain it for 4 hours.

9. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In step S4, primary drying is performed: the vacuum degree is set to 15 Pa, the partition temperature is raised to -15±2°C over 3 hours, and maintained for 4 hours after the ice crystals disappear.

10. The method for preparing tedizolid phosphate for injection according to claim 1, characterized in that: In step S4, secondary drying is performed: the partition temperature is raised to 0°C in 2 hours and maintained for 1 hour; the partition temperature is raised to 40±5°C in 5 hours and maintained for 20 hours, and the aeration is turned off and maintained for another 5 hours.

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