Preparation method of pazufloxacin mesylate injection

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly discloses a preparation method of pazufloxacin mesylate injection, which comprises the following steps: dissolving pazufloxacin mesylate and sodium chloride in water, regulating the pH value, removing impurities, filtering, filling and sealing, sterilizing, and keeping the temperature at 90-100 DEG C for not less than 6 hours. According to the method, the encapsulated pazufloxacin mesylate injection is placed in the hot air circulating oven after being sterilized, heat preservation is conducted for not less than 6 h at the temperature of 90-100 DEG C, the crystallization phenomenon before light inspection can be effectively avoided, the inherent quality of the pazufloxacin mesylate injection in the production process is guaranteed, medication safety is guaranteed, and the method has actual application and popularization value.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of pefazolin mesylate injection. BACKGROUND

[0002] Pefazolin mesylate injection is a broad-spectrum antibacterial drug, and the main component is pefazolin mesylate which belongs to quinolone antibiotics. The injection is slightly yellow, and is suitable for various infections caused by sensitive bacteria, including secondary infections of chronic respiratory diseases, pyelonephritis, complicated cystitis, prostatitis, burn wound infection, surgical wound infection, etc., and is widely used in clinical application.

[0003] The preparation process of pefazolin mesylate injection is a complex process involving multiple steps and strict quality control. The prevention of crystallization during preparation is an important link of quality control. Patent CN115919761B adds a stabilizer to the injection and adjusts the pH value to 3.5 to increase the solubility of the drug and reduce the occurrence of crystallization. However, the introduction of more excipients will increase the risk of side effects of the injection, and it is necessary to reduce the problem of crystallization in the preparation process of pefazolin mesylate injection by a safer, more effective and lower cost method. SUMMARY

[0004] To achieve the above-mentioned purpose, the application provides a preparation method of pefazolin mesylate injection, which is that pefazolin mesylate and sodium chloride are dissolved in water, the pH value is adjusted, impurities are removed, filtration is performed, sealing is performed, sterilization is performed, and the temperature is kept at 90-100 DEG C for not less than 6 hours.

[0005] Further, it specifically includes the following steps:

[0006] 1) Pefazolin mesylate and sodium chloride are respectively taken and dissolved in injection water to obtain pefazolin mesylate liquid and sodium chloride solution;

[0007] 2) The pefazolin mesylate liquid obtained in step 1) is taken and added to 1 / 3-2 / 3 of the total weight of injection water, and then the sodium chloride solution obtained in step 1) is added in sequence, and the injection water is added to 96-98% of the total weight, and the pH value is adjusted to 3.2-3.3 while stirring, and finally the volume is adjusted and stirred to obtain a liquid;

[0008] 3) Active carbon is taken and added to the liquid obtained in step 2) according to the mass ratio of 1:100-150 to obtain carbon slurry; the carbon slurry is added to the remaining liquid obtained in step 2), stirred, filtered with a decarburization filter for not less than 5 minutes, and then sequentially passes through a titanium filter and a polyvinylidene fluoride filter core with different pore sizes, and is sealed and sterilized;

[0009] 4) the sterilized solution of step 3) is placed in a hot air circulation oven at 90-100℃ for more than 6 hours, and the injection solution is obtained.

[0010] Further, the stirring speed is 40-80 r / min.

[0011] Further, the pH adjusting reagent of step 2) is hydrochloric acid solution.

[0012] Further, the concentration of the hydrochloric acid solution is 0.1 mol / L.

[0013] Further, the amount of the activated carbon of step 3) is 6 / 100-1 / 10 of the amount of the pazeramycin mesylate.

[0014] Further, the filtration of step 3) is sequentially through a 5 μm titanium filter, a 0.45 μm polyvinylidene fluoride filter core, a 0.22 μm polyvinylidene fluoride filter core and a 0.22 μm polyvinylidene fluoride terminal filter.

[0015] Further, the sterilization temperature of step 3) is 115℃, and the sterilization time is 30 min.

[0016] Further, the holding time of step 4) is 6-8 hours.

[0017] Further, the pazeramycin mesylate injection solution contains 30-50 g of pazeramycin mesylate and 4-5 g of sodium chloride per 1000 ml.

[0018] Further, the pazeramycin mesylate injection solution contains 30 g or 50 g of pazeramycin mesylate and 3 g of sodium chloride per 1000 ml.

[0019] In the process of realizing the present application, it is found in the laboratory small test stage that the pazeramycin mesylate injection solution prepared only with pazeramycin mesylate and sodium chloride as raw materials has crystal precipitation on some ampoule bottles in the later stage of the preparation process, i.e. in the lamp inspection stage, resulting in a low qualified rate of the injection solution passing the lamp inspection. In order not to affect the mass production of the injection solution, through the groping of the process steps, it is found that the injection solution after sealing is placed in a hot air circulation oven at a specific temperature for a specific time after sterilization, which can effectively avoid the crystal precipitation before the lamp inspection, and ensure the quality of the pazeramycin mesylate injection solution.

[0020] Through the actual workshop pilot test verification, the pazeramycin mesylate injection solution after sealing is placed in a hot air circulation oven at 90-100℃ for more than 6 hours after sterilization, which can effectively avoid the crystal precipitation before the lamp inspection, ensure the internal quality of the pazeramycin mesylate injection solution in the production process, guarantee the safety of drug use, and has practical popularization and application value.

[0021] Obviously, according to the above content of the present application, other various forms of modification, replacement or change can be made according to the common technical knowledge and usual means in the art without departing from the above basic technical idea of the present application.

[0022] The above content of the present application will be further explained in detail by a specific embodiment in the form of example. However, it should not be understood that the scope of the above subject matter of the present application is limited to the following example. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 Process flow chart. DETAILED DESCRIPTION

[0024] The raw materials, reagents and equipment used in the present application can be obtained by market purchase.

[0025] Example 1 Preparation of pefloxacin mesylate injection of the present application

[0026] Formulation:

[0027] Strength 2 ml: 0.1 g Pazufloxacin mesylate (as pazufloxacin) 50g Sodium chloride 4.8g Activated charcoal (for injection) 3g 0.1 mol / L hydrochloric acid solution q.s. Water for injection q.s. to 1000 mL

[0028] Preparation method:

[0029] 1) Weigh the raw materials according to the formulation; take pefloxacin mesylate and sodium chloride respectively, and dissolve in water for injection to obtain pefloxacin mesylate liquid and sodium chloride solution;

[0030] 2) Take the pefloxacin mesylate liquid obtained in step 1), add to 2 / 3 of the total weight of water for injection, and then sequentially add the sodium chloride solution obtained in step 1), water for injection to 96-98% of the total weight, stir at 60 r / min, and adjust the pH value to 3.2-3.3 with 0.1 mol / L hydrochloric acid, and finally add water for injection to the total amount of 1000 mL, and stir at 60 r / min for 30 min;

[0031] 3) Take activated carbon, add 1 g of activated carbon to 100 g of the liquid obtained in step 2) according to the mass ratio, to obtain carbon slurry; add the carbon slurry to the remaining liquid obtained in step 2), stir at 60 r / min for 15 min, then filter with a decarburization filter for not less than 5 minutes, and then sequentially pass through a 5 μm titanium filter, a 0.45 μm polyvinylidene fluoride filter core, a 0.22 μm polyvinylidene fluoride filter core and a 0.22 μm polyvinylidene fluoride terminal filter, and after filling and sealing, sterilize at a temperature of 115°C for 30 min;

[0032] 4) Place the liquid after sterilization in step 4) in a hot air circulating oven at 90°C for 8 hours, and obtain the product.

[0033] Example 2 Preparation of the pefloxacin mesylate injection of the present application

[0034] Formulation:

[0035] Strength 10 ml: 0.5 g Pazufloxacin mesylate (as pazufloxacin) 50g Sodium chloride 4.8g Activated charcoal (for injection) 3g 0.1 mol / L hydrochloric acid solution q.s. Water for injection q.s. to 1000 mL

[0036] Preparation method:

[0037] 1) Weigh the raw materials according to the formulation; take pefloxacin mesylate and sodium chloride respectively, dissolve in water for injection to obtain pefloxacin mesylate solution and sodium chloride solution;

[0038] 2) Take the pefloxacin mesylate solution obtained in step 1), add to 2 / 3 of the total weight of water for injection, then add the sodium chloride solution obtained in step 1) in turn, add water for injection to 96-98% of the total weight, stir at 60 r / min, adjust the pH value to 3.2-3.3 with 0.1 mol / L hydrochloric acid, finally add water for injection to the total amount of 1000 mL, stir at 60 r / min for 30 min;

[0039] 3) Take activated carbon, add 1 g of activated carbon to 150 g of the solution obtained in step 2) according to the mass ratio to obtain carbon slurry; add the carbon slurry to the remaining solution obtained in step 2), stir at 60 r / min for 15 min, then filter with a decarburization filter for not less than 5 minutes, and then pass through a 5 μm titanium filter, a 0.45 μm polyvinylidene fluoride filter, a 0.22 μm polyvinylidene fluoride filter and a 0.22 μm polyvinylidene fluoride terminal filter in turn, and sterilize at a temperature of 115°C for 30 min after filling and sealing;

[0040] 4) Put the solution after sterilization in step 4) into a hot air circulating oven at 100°C for 6 hours to obtain the product.

[0041] Example 3 Preparation of the pefloxacin mesylate injection of the present application

[0042] Formulation:

[0043] Strength 10 ml: 0.3 g Pazufloxacin mesylate (as pazufloxacin) 30g Sodium chloride 4.8g Activated charcoal (for injection) 3g 0.1 mol / L hydrochloric acid solution q.s. Water for injection q.s. to 1000 mL

[0044] 1) Weigh the raw materials according to the formulation; take pefloxacin mesylate and sodium chloride respectively, dissolve in water for injection to obtain pefloxacin mesylate solution and sodium chloride solution;

[0045] 2) Take the pefloxacin mesylate solution obtained in step 1), add to 2 / 3 of the total weight of water for injection, then add the sodium chloride solution obtained in step 1) in turn, add water for injection to 96-98% of the total weight, stir at 60 r / min, adjust the pH value to 3.2-3.3 with 0.1 mol / L hydrochloric acid, finally add water for injection to the total amount of 1000 mL, stir at 60 r / min for 30 min;

[0046] 3) Take activated carbon, add 1 g activated carbon to 110 g of the solution obtained in step 2) by mass ratio, to obtain a carbon slurry; add the carbon slurry to the remaining solution obtained in step 2), stir at 60 r / min for 15 min, then filter through a decarburization filter for not less than 5 min, and finally pass through a 5 μm titanium filter, a 0.45 μm polyvinylidene fluoride filter element, a 0.22 μm polyvinylidene fluoride filter element and a 0.22 μm polyvinylidene fluoride terminal filter in sequence, sterilize at 115°C for 30 min after filling and sealing;

[0047] 4) Place the solution obtained in step 4) after sterilization in a hot air circulating oven at 95°C for 7 hours, and obtain the product.

[0048] The beneficial effects of the present application are further illustrated by the following test examples:

[0049] Test Example 1 Preparation of pazeroxacin mesylate injection

[0050] I. Method

[0051] 1. Process flow

[0052] See the following table for details. Figure 1 .

[0053] 2. Preparation method

[0054] 2.1 Formulation information

[0055] Strength 2 ml: 0.1 g, 10 ml: 0.5 g 10 ml: 0.3 g Pazufloxacin mesylate (as pazufloxacin) 50g 30g Sodium chloride 4.8g 4.8g Activated charcoal (for injection) 3g 3g 0.1 mol / L hydrochloric acid solution q.s. q.s. Water for injection q.s. to 1000 mL q.s. to 1000 mL

[0056] 2.2 Method description

[0057] The batch prescription amount of material is weighed and moved to the liquid preparation room. The accumulated water in the liquid preparation tank and pipeline is drained as required, and the lower outlet valve of the liquid preparation tank is closed. The weighing system is peeled off, zeroed, and then about 2 / 3 of the total weight of the injection water is injected into the liquid preparation tank. A certain amount of injection water is added to the stainless steel barrel containing the pazeroxacin mesylate, and a certain amount of injection water is added to the stainless steel barrel containing the sodium chloride. After stirring to dissolve them thoroughly, the dissolved pazeroxacin mesylate solution is added to the liquid preparation tank. The preparation barrel is washed with injection water for not less than 2 times, and the dissolved sodium chloride solution is added to the liquid preparation tank. The preparation barrel is washed with injection water for not less than 2 times, and the washing water is added to the liquid preparation tank. The total weight of the injection water is added to the liquid preparation tank, and the stirring motor (speed about 60 r / min) is started. The pre-decarbonization (without titanium core) circulation is started for 10 min, and the original pH value of the liquid is tested and recorded. The pH value of the liquid is adjusted to 3.2-3.3 with 0.1 mol / L hydrochloric acid, and the total weight of the injection water is added after the pH value is adjusted. The liquid is stirred for 30 min. An appropriate amount of activated carbon is added to the liquid, and the carbon slurry is added to the liquid preparation tank. The barrel is washed with an appropriate amount of liquid for not less than 2 times, and the washing liquid is added to the liquid preparation tank. After 15 min of pre-decarbonization (without titanium core) stirring, the liquid is filtered through a decarbonization filter for not less than 5 min. At the same time, the sample is taken from the sampling port after the titanium filter to check the clarity of the liquid. After the liquid is clarified, it is filtered through a 5 μm titanium filter, a 0.45 μm polyvinylidene filter, a 0.22 μm polyvinylidene filter, and a 0.22 μm terminal filter (polyvinylidene material) to a liquid buffer tank in the filling and sealing room for filling and sealing.

[0058] The filled and sealed product is subjected to a final sterilization operation at a sterilization temperature of 115°C and a sterilization time of 30 min. After sterilization, the product is taken out and temporarily stored in the intermediate station for drying before the lamp inspection and packaging operation.

[0059] II. Results

[0060] Seventeen batches of pazeroxacin mesylate injection were produced, some of which were subjected to bottle drying operation in the intermediate station hot air circulating oven (temperature 40-70°C, 12-14 hours; temperature 90-100°C, 3-8 hours), and some of which were not subjected to bottle drying operation. The lamp inspection conditions are shown in Table 1.

[0061] Table 1 Lamp inspection conditions of pazeroxacin mesylate injection

[0062]

[0063] From Table 1 can be seen: after the preparation of pefloxacin mesylate injection, part of the ampoule will appear crystallization phenomenon, but if the filling and sealing after sterilization of pefloxacin mesylate injection, in 90~100 ℃ hot air circulation oven for 6~8 h, then light, packaging, delivery, can successfully solve the preparation process injection crystallization problem. After subsequent test again, filling and sealing after sterilization in 90~100 ℃ conditions for more than 8 hours although can reach similar effect, but due to the extension of the holding time will lead to significant increase in energy consumption, not conducive to industrial large-scale production of energy saving and efficiency. Therefore, the final determination of pefloxacin mesylate injection preparation process key control points for: filling and sealing after sterilization need to be in 90~100 ℃ environment for holding operation, time should be strictly controlled in 6~8 h, to ensure that the product quality meets the requirements.

Claims

1. A method for preparing pazufloxacin mesylate injection, characterized in that, It is made by dissolving pazufloxacin mesylate and sodium chloride in water, adjusting the pH value, removing impurities, filtering, filling, sterilizing, and keeping at 90-100℃ for no less than 6 hours.

2. The preparation method according to claim 1, characterized in that: It specifically includes the following steps: 1) Take pazufloxacin mesylate and sodium chloride separately, add water for injection to dissolve them, and obtain pazufloxacin mesylate solution and sodium chloride solution; 2) Take the pazufloxacin mesylate solution obtained in step 1) and add it to 1 / 3 to 2 / 3 of the total weight of water for injection. Then add the sodium chloride solution obtained in step 1) and water for injection until the total weight reaches 96 to 98%. While stirring, adjust the pH value to 3.2 to 3.

3. Finally, make up to volume and stir to obtain the drug solution. 3) Take activated carbon and add it to the drug solution obtained in step 2) at a mass ratio of 1:100-150 to obtain carbon slurry; add the carbon slurry to the remaining drug solution obtained in step 2), stir, filter and circulate it for no less than 5 minutes using a decarbonization filter, and finally pass it through a titanium filter and a polyvinylidene fluoride filter element with different pore sizes in sequence, and then fill and sterilize it. 4) Place the sterilized medicine solution from step 3) into a hot air circulating oven at 90-100℃ and keep it warm for no less than 6 hours to obtain the product.

3. The preparation method according to claim 2, characterized in that, The stirring speed is 40-80 r / min.

4. The preparation method according to claim 2, characterized in that, The reagent used to adjust the pH value in step 2) is hydrochloric acid solution.

5. The preparation method according to claim 4, characterized in that, The concentration of the hydrochloric acid solution is 0.1 mol / L.

6. The preparation method according to claim 2, characterized in that, Step 3) The amount of activated carbon used is 6 / 100 to 1 / 10 of the amount of pazufloxacin mesylate.

7. The preparation method according to claim 2, characterized in that, Step 3) The filtration process involves sequentially passing the material through a 5μm titanium filter, a 0.45μm polyvinylidene fluoride filter element, a 0.22μm polyvinylidene fluoride filter element, and a 0.22μm polyvinylidene fluoride terminal filter; the sterilization temperature is 115℃ and the time is 30 minutes.

8. The preparation method according to claim 2, characterized in that, Step 4) involves heat preservation for 6–8 hours.

9. The preparation method according to claim 2, characterized in that, The pazufloxacin mesylate injection contains 30-50g of pazufloxacin mesylate and 4-5g of sodium chloride per 1000ml.

10. The preparation method according to claim 9, characterized in that, The pazufloxacin mesylate injection contains 30g or 50g of pazufloxacin mesylate and 3g of sodium chloride per 1000ml.

Images