Linezolid sodium chloride injection and preparation method thereof

Abstract

The invention relates to the technical field of medicine preparation, and particularly discloses a linezolid sodium chloride injection and a preparation method thereof. According to the invention, the mixture of amino acid, ascorbyl palmitate and glycyrrhizic acid is adopted as the stabilizer, and the adding and mixing sequence of the main drug linezolid and other auxiliary materials is adjusted, so that the generation of a linezolid degradation impurity C in the preparation process of the injection is effectively reduced. The total impurity content in the injection is lower than 2.5%, the impurity C content is lower than 0.2%, and the stability of the main drug linezolid in the preparation process is remarkably improved. According to the linezolid sodium chloride injection, the problem that in the prior art, due to the fact that the chemical stability of the linezolid sodium chloride injection is poor, the impurity content is high in the storage process is effectively solved, and a new thought is provided for stability research of linezolid.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and specifically discloses a linezolid sodium chloride injection and a preparation method thereof. Background Art

[0002] Linezolid is a new synthetic oxazolidinone antibiotic and a bacterial protein synthesis inhibitor. It can be used to treat infections caused by aerobic Gram-positive bacteria, including suspected or confirmed hospital-acquired pneumonia (HAP) caused by MRSA, community-acquired pneumonia (CAP), complicated skin or skin and soft tissue infections (SSTI), and vancomycin-resistant enterococci (VRE) infections.

[0003] At present, the main ways of administering linezolid are oral and injection. Linezolid injection is a colorless to light brown clear liquid. Due to the poor chemical stability of linezolid and its sensitivity to light, acid, alkali and heat, improper storage can easily cause a high level of impurities in the injection, causing the color of the preparation to deepen and turn reddish brown. The main impurities involved in the quality control of linezolid injection are N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-(R)-hydroxypropyl]acetamide (impurity A) and N-[3-amino-2(S)-hydroxypropyl]-N-[[3-fluoro-4-(4-morpholinyl)]phenyl]acetamide (impurity B). In addition, linezolid injection also contains (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolin-2-one (impurity C), the chemical structure of which is as follows:

[0004] Since the generation of impurities is closely related to the preparation process of injection, it has been reported that the amount of activated carbon used can be increased when adsorbing linezolid injection to increase the adsorption of impurities. However, if the content of total impurities (including impurities A, B and C) is to be controlled below 2.5%, and the content of impurity C is to be controlled below 0.2%, a large amount of activated carbon must be used, and this amount of activated carbon is likely to cause a large loss of linezolid; there are also methods of adding metal ion chelating agents to the injection or replacing the citric acid-sodium citrate (citric acid-sodium citrate) buffer with buffer solutions with different buffering capacities such as disodium hydrogen phosphate-citric acid, acetic acid-sodium acetate, disodium hydrogen phosphate-potassium dihydrogen phosphate, etc., but it cannot avoid the situation where the product solution becomes darker and the content of impurity C is higher than 0.2% after the accelerated experiment.

[0005] Based on this, developing a highly stable linezolid sodium chloride injection has great practical significance for the research of linezolid preparations. Summary of the invention

[0006] In view of the problem that the chemical stability of linezolid sodium chloride injection is poor in the prior art and the impurity content is easily high during the storage process, the present invention provides a linezolid sodium chloride injection and a preparation method thereof. The present invention adopts a mixture of amino acids, ascorbyl palmitate and glycyrrhizic acid as a stabilizer, and by adjusting the order of adding and mixing the main drug linezolid and other auxiliary materials, the generation of linezolid degradation impurity C in the preparation process of the injection is effectively reduced, so that the total impurity content in the injection is less than 2.5%, and the impurity C content is less than 0.2%, which significantly improves the stability of the main drug linezolid in the preparation process, thereby effectively improving the chemical stability of linezolid sodium chloride injection.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions: The first aspect of the present invention provides a linezolid sodium chloride injection, wherein each 100 mL of the linezolid sodium chloride injection contains the following raw materials: 0.190 g to 0.220 g of linezolid, 0.885 g to 0.915 g of sodium chloride, 0.190 g to 0.195 g of anhydrous citric acid, 0.075 g to 0.077 g of sodium hydroxide, 0.002 g to 0.005 g of a stabilizer, and the remainder of water for injection; Wherein, the stabilizer is a mixture of amino acids, ascorbyl palmitate and glycyrrhizic acid.

[0008] Linezolid has poor stability. Under the conditions of high temperature or illumination, it is easy to react with free free radicals in the injection to cause its own degradation, so that the content of the main drug decreases, the impurity content increases, and the injection fails. The present invention uses a mixture of amino acids, ascorbyl palmitate and glycyrrhizic acid as a stabilizer, wherein ascorbyl palmitate has antioxidant properties, and can prevent the decomposition reaction of linezolid from being carried out by combining with free radicals, maintain the structure of linezolid, and ensure the chemical stability of the injection. The addition of amino acids can not only further enhance the effectiveness of ascorbyl palmitate, achieve the purpose of inhibiting the decomposition of linezolid, but also maintain the acid-base balance of the liquid, and ensure that linezolid will not decompose under this environment. Glycyrrhizic acid can act on the surface of drug molecules in part, and be dispersed in water for injection in part to form a mesh structure, capture drug molecules, prevent drug molecules from decomposing, and improve drug utilization while avoiding agglomeration, affecting the effectiveness of the injection. Through the synergistic effect of amino acids, palmitostearyl ascorbyl and glycyrrhizic acid, combined with other raw material components, the present invention can obtain a long-acting and stable linezolid sodium chloride injection, providing a new idea for the research and development of linezolid preparations.

[0009] Preferably, the amino acid is any one of histidine, lysine or arginine.

[0010] Preferably, the mass ratio of amino acid, palmityl ascorbyl and glycyrrhizic acid is 1:0.9:0.1-1:1.2:0.1.

[0011] The second aspect of the present invention provides a method for preparing the linezolid sodium chloride injection, comprising the following steps: Step 1: Dissolve the amino acid and ascorbyl palmitate in the first part of the water for injection according to the designed ratio, heat to 30°C-40°C, keep warm, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: Heat the second portion of water for injection to 60°C-70°C, add the prescribed amount of anhydrous citric acid and sodium hydroxide, dissolve, and filter to obtain a buffer solution; Step 3: dissolve the prescribed amount of linezolid in the buffer solution, add the stabilizer solution, sodium chloride and the remaining water for injection, adjust the pH value to 4.8-5.1, filter, fill and sterilize to obtain linezolid sodium chloride injection.

[0012] The present invention adds sodium chloride, anhydrous citric acid and sodium hydroxide to warm water for injection, removes impurities brought by auxiliary materials by filtering, and then adds stabilizer solution and linezolid. This order of adding materials can not only effectively avoid the problem that the auxiliary materials dissolve slowly and may carry impurities when the auxiliary materials are added together or in sequence, but also ensure the purity of linezolid injection. It also avoids the instability of the system containing linezolid and the mutual influence between the components, resulting in the problem of increased impurities of linezolid degradation.

[0013] More importantly, the present invention increases the temperature of the water for injection to 60°C-70°C, which also has a certain effect on controlling the impurity content. The present invention speculates that at this temperature, not only can the various auxiliary components be quickly dissolved, but also the citric acid and the sodium citrate generated by the reaction with sodium hydroxide can exert their buffering capacity, which is beneficial to the overall pH stability of the injection. At the same time, linezolid can maintain stability in the buffer solution and will not decompose, effectively reducing the impurity content generated by decomposition.

[0014] Preferably, in step 1, the first portion of water for injection accounts for 10%-15% of the volume of the water for injection.

[0015] Preferably, in step 1, the insulation time is 30 min-50 min.

[0016] Preferably, in step 2, the second portion of water for injection accounts for 50%-70% of the volume of the water for injection.

[0017] Preferably, in step 2, the filtration is performed using a semipermeable membrane with a pore size of 100nm-300nm.

[0018] Preferably, in step three, the filtration is carried out in a two-stage filtration mode; wherein the pore size of the first stage filtration is 0.4 μm-0.5 μm; and the pore size of the second stage filtration is 0.2 μm-0.25 μm.

[0019] Further preferably, in step three, the filter element for the first stage filtration and the filter element for the second stage filtration are both polyethersulfone.

[0020] The present invention adopts secondary filtration with specific pore size and specific filter element, adopts polyethersulfone with larger pore size for preliminary filtration to remove impurities in injection solution, and then adopts polyethersulfone with smaller pore size for terminal filtration to remove heat source and endotoxin in injection solution for sterilization, and combines the addition and mixing sequence of specific main drug linezolid and other auxiliary materials, so as to further reduce the generation of linezolid degradation impurity C in the preparation process and improve the efficiency of sterilization.

[0021] Preferably, in step 4, the sterilization temperature is 118°C-122°C, and the sterilization time is 10min-15min.

[0022] In summary, the present invention provides a linezolid sodium chloride injection, which uses a mixture of amino acids, ascorbyl palmitate and glycyrrhizic acid as a stabilizer, and by adjusting the order of adding and mixing the main drug linezolid and other excipients, effectively reduces the generation of linezolid degradation impurity C in the preparation process of the injection, improves the stability of the main drug linezolid, and thus effectively improves the chemical stability of linezolid sodium chloride injection. The technical solution of the present invention effectively solves the problem in the prior art that the chemical stability of linezolid sodium chloride injection is poor, and the impurity content is easily high during storage. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0024] Example 1 This embodiment provides a linezolid sodium chloride injection, which specifically includes the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:1:0.1.

[0025] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine and ascorbyl palmitate in 10% volume of water for injection, heat to 35°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 65°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0026] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0027] Example 2 This embodiment provides a linezolid sodium chloride injection, which specifically includes the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: linezolid 0.200 g, anhydrous citric acid 0.192 g, sodium chloride 0.900 g, sodium hydroxide 0.076 g, stabilizer 0.002 g and the balance water for injection; Wherein, the stabilizer is lysine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:1.2:0.1.

[0028] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve lysine and ascorbyl palmitate in 15% volume of water for injection, heat to 40°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilized solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 60% volume of water for injection to 65°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0029] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0030] Example 3 This embodiment provides a linezolid sodium chloride injection, which specifically includes the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.192 g of anhydrous citric acid, 0.900 g of sodium chloride, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:0.9:0.1.

[0031] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine and ascorbyl palmitate in 15% volume of water for injection, heat to 40°C, keep warm for 35 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilized solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 60% volume of water for injection to 85°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 300 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 4.9, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 15 min, and obtaining linezolid sodium chloride injection.

[0032] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 4.9. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0033] Example 4 This embodiment provides a linezolid sodium chloride injection, which is different from Example 1 in that, in step 2, the temperature of the injection water is heated to 85° C., and other components and processes remain unchanged, specifically including the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:1:0.1.

[0034] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine and ascorbyl palmitate in 10% volume of water for injection, heat to 35°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 85°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0035] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0036] Example 5 This embodiment provides a linezolid sodium chloride injection, which is different from Example 1 in that the order of adding materials is changed, and other components and processes remain unchanged, and specifically includes the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:1:0.1.

[0037] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine and ascorbyl palmitate in 10% volume of water for injection, heat to 35°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 65°C, add anhydrous citric acid, sodium hydroxide and stabilizer, dissolve and purify with OC1074 strong basic anion resin to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 15 min, and obtaining linezolid sodium chloride injection.

[0038] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0039] Example 6 This embodiment provides a linezolid sodium chloride injection, which is different from embodiment 1 in that: the stabilizer is histidine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:1.5:0.1, and specifically includes the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine, ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:1.5:0.1.

[0040] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine and ascorbyl palmitate in 10% volume of water for injection, heat to 35°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 65°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0041] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0042] Comparative Example 1 This comparative example provides a linezolid sodium chloride injection, which is different from Example 1 in that: the stabilizer is histidine and ascorbyl palmitate in a mass ratio of 1:1, and other ingredients and processes remain unchanged, specifically including the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine and ascorbyl palmitate in a mass ratio of 1:1.

[0043] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine and ascorbyl palmitate in 10% volume of water for injection, heat to 35°C, and keep warm for 30 minutes to obtain a stabilizing solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 65°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0044] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0045] Comparative Example 2 This comparative example provides a linezolid sodium chloride injection, which is different from Example 1 in that: the stabilizer is histidine and glycyrrhizic acid in a mass ratio of 1:0.1, and the other ingredients and processes remain unchanged, specifically including the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is histidine and glycyrrhizic acid in a mass ratio of 1:0.1.

[0046] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve histidine in 10% volume of water for injection, heat to 35°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 65°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0047] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0048] Comparative Example 3 This comparative example provides a linezolid sodium chloride injection, which is different from Example 1 in that: the stabilizer is ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:0.1, and other ingredients and processes remain unchanged, specifically including the following contents: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: 0.200 g of linezolid, 0.900 g of sodium chloride, 0.192 g of anhydrous citric acid, 0.076 g of sodium hydroxide, 0.005 g of stabilizer and the balance of water for injection; Wherein, the stabilizer is ascorbyl palmitate and glycyrrhizic acid in a mass ratio of 1:0.1.

[0049] The preparation method of the linezolid sodium chloride injection comprises the following steps: Step 1: Weigh the component raw materials of the stabilizer according to the designed ratio, dissolve ascorbic acid palmitate in 10% volume of water for injection, heat to 35°C, keep warm for 30 minutes, then add glycyrrhizic acid, mix well, and obtain a stabilized solution; Step 2: Weigh all the raw materials except the stabilizer according to the designed ratio, heat 50% volume of water for injection to 65°C, add anhydrous citric acid and sodium hydroxide, and filter through a semipermeable membrane with a pore size of 200 nm after dissolution to obtain a buffer solution; Step 3, dissolving linezolid in the buffer solution, adding the stabilizing solution, sodium chloride and the remaining water for injection, adjusting the pH value to 5.0, filtering through a polyethersulfone filter element with a pore size of 0.45 μm and a polyethersulfone filter element with a pore size of 0.22 μm to obtain a filtrate; filling the filtrate, sterilizing at 121° C. for 10 min, and obtaining linezolid sodium chloride injection.

[0050] The above-mentioned linezolid sodium chloride injection is a colorless clear liquid with a pH of 5.0. It was tested according to the membrane filtration method under the sterility test item in the 2015 edition of the Chinese Pharmacopoeia, and the results were in compliance with the regulations. According to the gel method test under the bacterial endotoxin item in the 2015 edition of the Chinese Pharmacopoeia, the bacterial endotoxins were in compliance with the regulations.

[0051] In order to further confirm the technical effect of the present invention, the present invention conducted a stability study on the linezolid sodium chloride injection prepared in each embodiment and comparative example, and carried out liquid chromatography detection at 25°C under light-proof conditions, wherein the results of the detection of the contents of impurity A, impurity B, impurity C and linezolid are shown in Table 3. Among them, the linezolid reference substance was purchased from the China Food and Drug Inspection Institute, batch number 130640-201901, with a content of 99.6%; N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]amino]-2-(R)-hydroxypropyl]acetamide (impurity A) reference substance was purchased from QCC, product number: QL142607, content 98%; N-[3-amino-2(S)-hydroxypropyl]-N-[[3-fluoro-4-(4-morpholinyl)]phenyl]acetamide (impurity B) The reference substance was purchased from QCC, product number QL122605, with a content of 98%; (S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolin-2-one (Impurity C) reference substance was purchased from USP, batch number R088P0, with a content of 100%.

[0052] 1.1. Detection method for the content of related substances (impurity A, impurity B, other single impurities, total amount of impurities) in linezolid sodium chloride injection (1) Mobile phase Mobile phase A: Accurately measure 10 mL of 10% trifluoroacetic acid solution and add it to 1000 mL of water, and filter it through a 0.45 μm membrane filter; Mobile phase B: Accurately measure 10 mL of 10% trifluoroacetic acid solution and add it to 1000 mL of acetonitrile, and filter it through a 0.45 μm membrane filter; Diluent: acetonitrile-water (10:90).

[0053] (2) Test solution: Take this product as the test solution.

[0054] (3) Control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL volumetric flask. Dissolve it in diluent and dilute to the mark. Shake well.

[0055] (4) Chromatographic conditions Chromatographic column: YMC-Pack ODS-AM (150×4.6mm, 5μm) Column temperature: room temperature Detection wavelength: 254nm Flow rate: 1.0mL / min Injection volume: 10 μL Elution method: gradient elution. The elution program is shown in Table 1.

[0056] Table 1 Elution program

[0057] (5) Sample testing Accurately measure 10 μL of diluent, test solution and control solution respectively, inject and measure, deduct the blank solvent peak, and calculate the amount of related substances by the self-control method.

[0058] 1.2. Determination of Linezolid Content in Linezolid Sodium Chloride Injection (1) Mobile phase Mobile phase A: Accurately measure 10 mL of 10% trifluoroacetic acid solution and add it to 1000 mL of water, and filter it through a 0.45 μm membrane filter; Mobile phase B: Accurately measure 10 mL of 10% trifluoroacetic acid solution and add it to 1000 mL of acetonitrile, and filter it through a 0.45 μm membrane filter; Mobile phase: mobile phase A-mobile phase B (80:20); Diluent: acetonitrile-water (10:90).

[0059] (2) Test solution: Accurately measure 5 mL of the product and place it in a 100 mL volumetric flask. Dilute to the mark with diluent and shake well.

[0060] (3) Reference solution: Accurately weigh about 10 mg of linezolid reference substance and place it in a 100-mL volumetric flask. Add 10 mL of acetonitrile to dissolve it. Add water to dilute to the mark and shake well.

[0061] (4) Chromatographic conditions Chromatographic column: YMC-Pack ODS-AM (150×4.6mm, 5μm) Column temperature: room temperature Detection wavelength: 254nm Flow rate: 1.0mL / min Injection volume: 10 μL Running time: 10 minutes.

[0062] (5) Sample testing Accurately measure 10 μL of the reference solution and the test solution respectively, and inject them for determination, and calculate the content according to the external standard method.

[0063] 1.3. Determination of Impurity C in Linezolid Sodium Chloride Injection (1) Mobile phase Mobile phase A: Accurately measure 10 mL of 10% trifluoroacetic acid solution and add it to 1000 mL of water, and filter it through a 0.45 μm membrane filter; Mobile phase B: Accurately measure 10 mL of 10% trifluoroacetic acid solution and add it to 1000 mL of acetonitrile, and filter it through a 0.45 μm membrane filter; Diluent: acetonitrile-water (10:90).

[0064] (2) Test solution: Accurately measure 5 mL of the product and place it in a 100 mL volumetric flask. Dilute to the mark with diluent and shake well.

[0065] (3) Reference solution: Accurately weigh about 10 mg of impurity C reference substance and place it in a 100 mL volumetric flask. Add 10 mL of acetonitrile to dissolve it. Add water to dilute to the mark and shake well.

[0066] (4) Chromatographic conditions Chromatographic column: Gemini C18 column (150×4.6mm, 5μm) Column temperature: room temperature Detection wavelength: 254nm Flow rate: 1.0mL / min Injection volume: 10 μL Running time: 10 minutes; Elution method: gradient elution. The elution program is shown in Table 2.

[0067] Table 2 Elution program

[0068] (5) Sample testing Accurately measure 10 μL of the reference solution and the test solution respectively, and inject them for determination, and calculate the content according to the external standard method.

[0069] In order to further verify the stability of the linezolid sodium chloride injection provided by the present invention, the stability test of the linezolid sodium chloride injection obtained in each example and the comparative example was carried out, and the linezolid sodium chloride injection obtained in each example and the comparative example was stored for 15 days under the conditions of 25°C in the dark, 60°C in the dark, and 25°C illumination (light intensity of 4500Lux), respectively. The detection results of impurity A, impurity B, impurity C, the total content of related substances and the content of linezolid are shown in Tables 4-7.

[0070] Table 3 Stability test of the injections obtained from each embodiment and each comparative example at 25°C and protected from light for 0 days

[0071] Table 4 Stability test of the injections obtained from the examples and comparative examples after 15 days of exposure to light at 25°C

[0072] It can be seen from Table 3 and Table 4 that, after being placed for 15 days at 25° C. in the dark, the total amount of impurities in the linezolid sodium chloride injection obtained in Example 1 increased by only 0.03%, and the linezolid content decreased by only 0.01%. It can be seen that at 25° C. in the dark, the linezolid sodium chloride injection obtained in Example 1 has good stability.

[0073] Table 5 Stability test of the injections obtained from the embodiments and comparative examples at 60°C and protected from light for 0 d

[0074] Table 6 Stability test of the injections obtained in each embodiment and each comparative example after 15 days at 60°C in dark

[0075] It can be seen from Tables 5 and 6 that, after being placed for 15 days at 60° C. in the dark, the total amount of impurities in the linezolid sodium chloride injection obtained in Example 1 increased by only 0.17%, and the linezolid content decreased by only 0.2%. It can be seen that at 60° C. in the dark, the linezolid sodium chloride injection obtained in Example 1 has good stability.

[0076] Table 7 Stability test of the injections obtained from the embodiments and comparative examples after 25°C illumination for 0 days

[0077] Table 8 Stability test of the injections obtained in each embodiment and each comparative example after irradiation at 25°C for 15 days

[0078] It can be seen from Tables 7 and 8 that under 25°C light conditions, after being placed for 15 days, the total amount of impurities in the linezolid sodium chloride injection obtained in Example 1 only increased by 0.12%, and the linezolid content only decreased by 0.1%. It can be seen that under 25°C light conditions, the linezolid sodium chloride injection obtained in Example 1 has good stability.

[0079] It can be seen that the present invention effectively controls the generation of linezolid impurities and the decomposition of linezolid in the entire preparation process by adjusting the mixing order of the auxiliary materials and the main drug linezolid and limiting the temperature of the water for injection, thereby increasing the stability of the linezolid sodium chloride injection.

[0080] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A linezolid sodium chloride injection, Features: Each 100 mL of linezolid sodium chloride injection contains the following raw materials: linezolid 0.190g-0.220g, sodium chloride 0.885g-0.915g, anhydrous citric acid 0.190g-0.195g, sodium hydroxide 0.075g-0.077g and stabilizer 0.002g-0.005g; Wherein, the stabilizer is a mixture of amino acids, ascorbyl palmitate and glycyrrhizic acid.

2. The linezolid sodium chloride injection according to claim 1, Features: The amino acid is any one of histidine, lysine or arginine.

3. The linezolid sodium chloride injection according to claim 1 or 2, Features: The mass ratio of amino acid, palmitostearyl ascorbyl and glycyrrhizic acid is 1:0.9:0.1-1:1.2:0.

1.

4. A method for preparing the linezolid sodium chloride injection according to any one of claims 1 to 3, Features: The steps include: Step 1: Dissolve the amino acid and ascorbyl palmitate in the first part of the water for injection according to the designed ratio, heat to 30°C-40°C, keep warm, then add glycyrrhizic acid, mix well, and obtain a stabilizer solution; Step 2: Heat the second portion of water for injection to 60°C-70°C, add the prescribed amount of anhydrous citric acid and sodium hydroxide, dissolve, and filter to obtain a buffer solution; Step 3: dissolve the prescribed amount of linezolid in the buffer solution, add the stabilizer solution, sodium chloride and the remaining water for injection, adjust the pH value to 4.8-5.1, filter, fill and sterilize to obtain linezolid sodium chloride injection.

5. The method for preparing linezolid sodium chloride injection according to claim 4, Features: In step 1, the first portion of water for injection accounts for 10%-15% of the total volume of water for injection; and / or In step 1, the insulation time is 30min-50min.

6. The method for preparing linezolid sodium chloride injection according to claim 4, Features: In step 2, the second portion of water for injection accounts for 50%-70% of the total volume of water for injection; and / or In step 2, the filtration is performed using a semipermeable membrane with a pore size of 100nm-300nm.

7. The method for preparing linezolid sodium chloride injection according to claim 4, Features: In step three, the filtration is carried out in a two-stage filtration mode; wherein the pore size of the first-stage filtration is 0.4 μm-0.5 μm; and the pore size of the second-stage filtration is 0.2 μm-0.25 μm.

8. The method for preparing linezolid sodium chloride injection according to claim 7, Features: In step three, the filter element of the first-stage filtration and the filter element of the second-stage filtration are both polyethersulfone.

9. The method for preparing linezolid sodium chloride injection according to claim 4, Features: In step three, the sterilization temperature is 118°C-122°C, and the sterilization time is 8min-12min.

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