Preparation method of famotidine injection

Abstract

The invention relates to the technical field of biological medicine, and discloses a famotidine injection preparation method, which comprises: S1, lactic acid pretreatment: weighing lactic acid, diluting with injection water, carrying out high temperature treatment, and sealing and storing the treated lactic acid solution for spare; s2, liquid medicine preparation: S201, adding water for injection into a concentrated preparation tank, introducing nitrogen, and starting stirring; s202, adding water for injection into a diluting tank, introducing nitrogen, adding the lactic acid solution pretreated in the step S1 and famotidine, and stirring for dissolving; s203, sequentially adding nicotinamide, mannitol and vitamin C; s204, supplementing the water for injection to the total amount; s205, inputting into a buffer tank for later use; s3, bottle washing; s4, performing filling; s5, performing leak detection; and S6, light inspection and packaging. Nitrogen protection is introduced in the liquid medicine preparation and filling process, and multi-stage filtration is adopted, so that degradation caused by oxidation or microbial contamination in the production process of famotidine is reduced.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and particularly to a preparation method of famotidine injection. Background Art

[0002] Famotidine is an H2 receptor antagonist, commonly used for treating peptic ulcers and gastroesophageal reflux disease caused by excessive gastric acid. Its injection form has the advantage of rapid onset in clinical practice. Currently, the preparation method of famotidine injection generally includes steps such as liquid medicine preparation, filtration, filling, and sterilization. In the prior art, during the preparation process, the active ingredient and excipients are usually dissolved with water for injection, and then particles and microorganisms are removed through single-stage filtration (such as a 0.22 μm filter element). After filling, sterilization treatment is carried out to obtain the finished product. Such processes have been widely used in industrial production and can meet basic quality requirements, such as the content conforming to the range of 90.0% - 110.0% specified in the pharmacopoeia.

[0003] However, the prior art has deficiencies in the control of liquid medicine stability. Due to the ineffective control of dissolved oxygen content during the preparation and filling processes, famotidine is prone to react with oxygen, resulting in oxidative degradation. Especially when stored for a long time or exposed to air during the production process, the content may drop below 90.0%, affecting the drug activity. In addition, the single-stage filtration process has limited ability to remove microorganisms and fine particles, and potential contamination risks may still remain in the liquid medicine after filtration. Especially, the microbial load may reach more than 20 CFU / 100 ml before terminal filtration. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the present invention provides a preparation method of famotidine injection, which solves the problem that in the prior art, due to the ineffective control of dissolved oxygen content during the preparation and filling processes, famotidine is prone to react with oxygen, resulting in oxidative degradation.

[0005] To achieve the above objectives, the present invention is realized through the following technical solutions: A preparation method of famotidine injection, comprising the following steps:

[0006] S1, Pretreatment of lactic acid: Weigh lactic acid, dilute it with water for injection, and perform high-temperature treatment. Detect that the content of lactic acid monomer is not less than 96.5%. The treated lactic acid solution is stored in a sealed manner for later use;

[0007] S2, Liquid medicine preparation

[0008] S201, Add water for injection into the concentrated preparation tank, introduce nitrogen, and start stirring;

[0009] S202, Add water for injection into the diluted preparation tank, introduce nitrogen, add the lactic acid solution pretreated in step S1 and famotidine, and stir to dissolve;

[0010] S203: Add niacinamide, mannitol, and vitamin C in sequence, stir to dissolve, take samples for determination and adjust the pH value.

[0011] S204: Make up to the full volume with injection water. After the liquid medicine is circulated and filtered through a filter element, it is filtered into a storage tank, and nitrogen is introduced to maintain positive pressure.

[0012] S205: The liquid medicine in the storage tank is filtered through a filter element and input into a buffer tank for standby.

[0013] S3: Wash the bottles. Use filtered purified water, injection water, and compressed air to wash the ampoules, and perform drying and sterilization in an oven.

[0014] S4: Fill. The liquid medicine is filled with nitrogen from the buffer tank.

[0015] S5: Leak detection. Use carmine solution for leak detection.

[0016] S6: Lamp inspection and packaging. After lamp inspection, the unqualified products are removed and packaged to obtain the finished products.

[0017] Preferably, in step S1, the lactic acid is diluted with injection water at a mass ratio of 1:6, and the high-temperature treatment conditions are 115 - 125°C for 170 - 190 minutes. The treated lactic acid solution is stored in a sealed manner at room temperature for no more than 35 - 40 hours.

[0018] Preferably, in step S201, the injection water is 145 - 155% of the preparation amount, the stirring speed is 58 - 62 revolutions per minute, the water temperature is controlled at 20 - 30°C, and the dissolved oxygen ≤ 1.0 mg / L.

[0019] In step S202, the injection water is 65 - 75% of the preparation amount, and the stirring and dissolving time of famotidine is 20 - 25 minutes.

[0020] Preferably, in step S203, the stirring and dissolving time of niacinamide, mannitol, and vitamin C is 8 - 12 minutes, and the pH value is adjusted to 6.0 - 6.2. If the pH value is not within this range, use 0.4 - 0.6 mol / L sodium hydroxide solution for adjustment.

[0021] In step S204, the filter element is 0.45 μm and 0.22 μm polyethersulfone filter elements, the circulating filtration time is 30 - 40 minutes, and the amount of injection water made up to the full volume is 460 - 462 kg.

[0022] Preferably, in step S205, the filter element is two 0.22 μm polyethersulfone filter elements, the filtration temperature ≤ 30°C, the filtration time ≤ 10 hours, the pressure difference between the terminal filter and the pipeline ≤ 0.20 MPa, and the bubble point pressure of the filter element integrity test ≥ 0.35 MPa.

[0023] Preferably, in step S3, the pressure of purified water is 0.25 - 0.50 MPa, the pressure of injection water is 0.10 - 0.30 MPa, the pressure of compressed air is 0.25 - 0.70 MPa, the drying and sterilization temperature of the oven is set at 290 - 310 °C, the monitored temperature ≥ 285 °C, and the storage time limit after ampoule sterilization does not exceed 1.5 - 2.5 hours.

[0024] Preferably, in step S4, the filling volume is controlled at 2.15 - 2.23 ml, the target filling volume is 2.18 - 2.20 ml, the residual oxygen rate ≤ 1.0%, the filling speed is 540 - 560 vials / minute, and the first 1200 - 1400 vials of liquid medicine are discarded.

[0025] Preferably, in step S5, the concentration of carmine solution ≥ 0.2 g / L, the leak detection conditions are first negative pressure ≤ -80 kPa for ≥ 8 - 12 minutes, then positive pressure ≥ +80 kPa for ≥ 8 - 12 minutes, and leaks with a pore diameter of 5 μm and above can be detected.

[0026] Preferably, the specification of the famotidine injection is 2 ml:20 mg, the preparation batch is 450 - 470 L, and the packaging form in step S6 is 10 - 14 vials / box.

[0027] Preferably, the storage time limit of the storage tank does not exceed 10 - 12 hours, the storage time limit of the liquid medicine does not exceed 11 - 13 hours, the total production time limit does not exceed 15 - 16 hours, the yield ≥ 87.0%, the microbial load of the liquid medicine before terminal filtration in step S205 ≤ 10 CFU / 100 ml, and the bacterial endotoxin of the filling sample in step S4 < 7.5 EU / mg.

[0028] The present invention provides a preparation method of famotidine injection. It has the following beneficial effects:

[0029] 1. By introducing nitrogen protection and adopting multi-stage filtration (0.45 μm and 0.22 μm polyethersulfone filters) during the preparation and filling of the liquid medicine, the present invention effectively reduces the dissolved oxygen content to ≤ 1.0 mg / L, and further sterilizes through two 0.22 μm terminal filters, reducing the degradation of famotidine caused by oxidation or microbial contamination during the production process.

[0030] 2. By subjecting lactic acid to high-temperature treatment at 115 - 125 °C for 170 - 190 minutes, the present invention ensures that the lactic acid monomer content is not less than 96.5%, and enhances its compatibility with famotidine under the dilution ratio of 1:6, reducing the interference of potential impurities in lactic acid on the stability of the liquid medicine.

[0031] 3. During the preparation process of the present invention, the pH value is adjusted to 6.0 - 6.2, and the filling volume is controlled within the range of 2.15 - 2.23 ml through nitrogen filling, which optimizes and ensures the consistency of the acidity and alkalinity and dosage of famotidine injection among different batches, and reduces the change in drug activity caused by pH fluctuations or filling volume deviations.

[0032] 4. By limiting the storage time limit of the storage tank (10 - 12 hours), the storage time limit of the liquid medicine (11 - 13 hours), and the total production time limit (15 - 16 hours), and combining with the high - efficiency filtration and filling process, the present invention increases the finished product rate to ≥87.0%, reduces the loss caused by the long - term exposure of the liquid medicine, and improves the production efficiency at the same time.

[0033] 5. Through multi - stage filtration and strict aseptic operation, the present invention controls the microbial load of the liquid medicine before terminal filtration to ≤10 CFU / 100 ml, and the bacterial endotoxin content of the filling sample to <7.5 EU / mg, which has improvements in sterility and safety and reduces the potential risks in clinical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a process flow chart of a preparation method of a famotidine injection of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0035] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts belong to the scope of protection of the present invention.

[0036] Please refer to the attached Figure 1 , the embodiment of the present invention provides a preparation method of a famotidine injection, including the following steps:

[0037] S1. Pretreatment of lactic acid: Weigh lactic acid, dilute it with water for injection and then perform high - temperature treatment. Detect that the content of lactic acid monomer is not less than 96.5%. The treated lactic acid solution is stored in a sealed manner for later use;

[0038] S2. Preparation of the liquid medicine

[0039] S201. Add water for injection into the concentrated mixing tank, introduce nitrogen, and start stirring;

[0040] S202. Add water for injection into the dilute mixing tank, introduce nitrogen, add the lactic acid solution pretreated in step S1 and famotidine, and stir to dissolve;

[0041] S203. Add niacinamide, mannitol, and vitamin C in sequence, stir to dissolve, take samples for measurement, and adjust the pH value.

[0042] S204. Make up the volume to the full amount with injection water. After the liquid medicine is filtered by circulating through the filter element, it is filtered into the storage tank, and nitrogen is introduced to maintain positive pressure.

[0043] S205. The liquid medicine in the storage tank is filtered by the filter element and input into the buffer tank for standby.

[0044] S3. Wash the vials. Use the filtered purified water, injection water, and compressed air to wash the ampoules, and then carry out drying and sterilization in the oven.

[0045] S4. Fill. The liquid medicine is filled while nitrogen is introduced from the buffer tank.

[0046] S5. Leak detection. Use carmine solution for leak detection.

[0047] S6. Lamp inspection and packaging. After lamp inspection, the unqualified products are removed and then packaged to obtain the finished products.

[0048] Specifically, in step S1, lactic acid is diluted with injection water at a mass ratio of 1:6, and the high-temperature treatment conditions are 115 - 125 °C for 170 - 190 minutes. The treated lactic acid solution is stored in a sealed manner at room temperature for no more than 35 - 40 hours. In step S2, the formulation process adopts separate tank operation. The concentrated formulation tank and the dilute formulation tank undertake different functions respectively. The concentrated formulation tank is mainly used for preparing the initial dissolution environment, while the dilute formulation tank completes the mixing of the active ingredients and excipients. This step-by-step formulation method can effectively avoid drug degradation caused by excessive local concentration. Nitrogen introduction runs through the whole formulation and filling process, reducing oxidation reactions by decreasing the oxygen content to ensure the chemical stability of the liquid medicine. In step S3, the vial washing process not only cleans the ampoules but also completely eliminates the microbial pollution source through high-temperature sterilization, providing a clean container for subsequent filling. The nitrogen-introduced filling design in step S4 further protects the liquid medicine from air oxidation and ensures the accuracy of the filling volume. In step S5, the pressure change of the carmine solution is used to detect the sealability of the ampoules to ensure that the products do not leak during storage and transportation. The lamp inspection and packaging in step S6 serve as the final quality control link. Defective products with appearance defects are removed by manual or automated means, and reasonable packaging forms are adopted for convenient clinical use. Each step of this method has been optimized and works synergistically to improve product quality and production efficiency.

[0049] In step S1, lactic acid is diluted with injection water at a mass ratio of 1:6, and the high-temperature treatment conditions are 115 - 125 °C for 170 - 190 minutes. The treated lactic acid solution is stored in a sealed manner at room temperature for no more than 35 - 40 hours.

[0050] Specifically, the setting of diluting lactic acid at a mass ratio of 1:6 in step S1 is based on the solubility characteristics of lactic acid and the requirements of subsequent high-temperature treatment. This ratio can ensure the full dispersion of lactic acid in water, avoid the situation of overly strong local acidity due to too high concentration, and at the same time provide a uniform solution environment for high-temperature treatment. The selection of the high-temperature treatment temperature range of 115 - 125 °C takes into account the stability of the lactic acid molecular structure. Within this range, it can effectively decompose potential polymers or impurities without destroying the lactic acid monomer itself. The treatment time of 170 - 190 minutes is the optimal duration range verified in experiments, which can ensure that the lactic acid monomer content meets the requirements while avoiding energy waste or by-product generation caused by overlong heating. The standard for detecting that the lactic acid monomer content is not less than 96.5% is determined by high-performance liquid chromatography. This index is directly related to the effect of lactic acid as a stabilizer in the medicinal solution. The design that the sealed storage time of the treated lactic acid solution does not exceed 35 - 40 hours is based on the stability study of the lactic acid solution under normal temperature conditions. If it exceeds this time, the quality may be affected due to microbial growth or chemical degradation. Therefore, it needs to be used for formulation as soon as possible within this time range to ensure the smooth progress of subsequent processes.

[0051] In step S201, the amount of water for injection is 145 - 155% of the preparation volume, the stirring speed is 58 - 62 revolutions per minute, the water temperature is controlled at 20 - 30 °C, and the dissolved oxygen ≤ 1.0 mg / L;

[0052] In step S202, the amount of water for injection is 65 - 75% of the preparation volume, and the stirring and dissolving time of famotidine is 20 - 25 minutes.

[0053] Specifically, in step S201, the amount of water for injection is 145 - 155% of the preparation volume. The selection of this range is based on the volume design of the concentrated preparation tank and the initial dilution requirements of the medicinal solution preparation. Too little water may lead to uneven stirring, and too much may reduce the dilution efficiency and affect the accuracy of subsequent water replenishment steps. The setting of the stirring speed of 58 - 62 revolutions per minute is obtained through experimental optimization. This range can form a stable vortex, ensure the uniform distribution of nitrogen in water, and at the same time avoid foam generation caused by too high a speed or insufficient mixing caused by too low a speed. Controlling the water temperature at 20 - 30 °C is to maintain the mildness of the medicinal solution preparation environment. Too low a temperature may slow down the dissolution rate, and too high a temperature may accelerate the oxidation reaction and affect the stability of famotidine. The requirement of dissolved oxygen ≤ 1.0 mg / L is achieved by introducing nitrogen. Nitrogen not only replaces the oxygen in water but also forms a protective atmosphere throughout the preparation process. The control of this parameter is directly related to the antioxidant performance of the medicinal solution. After multiple experiments and verifications, this limit value can significantly reduce the degradation of active ingredients;

[0054] In step S202, the injection water volume is 65-75% of the formulation amount. This range is designed considering the capacity of the dilute formulation tank and the dissolution requirements of famotidine and lactic acid solution, aiming to reserve sufficient space for subsequent excipient addition and avoid the precipitation risk caused by too high a drug solution concentration. Introducing nitrogen continues to play a protective role in this step. By creating a low-oxygen environment in the dilute formulation tank, the opportunity for the drug solution to contact air is further reduced. The selection of the stirring and dissolution time of famotidine for 20-25 minutes is based on its dissolution rate experimental data. This time range can ensure that famotidine is completely dissolved and uniformly mixed with lactic acid, while avoiding mechanical stress caused by too long stirring or incomplete dissolution caused by too short a time. During the stirring process, the sealing design of the dilute formulation tank and the control of nitrogen flow rate are particularly important. An appropriate nitrogen flow rate can maintain a slightly positive pressure in the tank, protecting the drug solution and facilitating subsequent operations.

[0055] In step S203, the stirring and dissolution time of niacinamide, mannitol, and vitamin C is 8-12 minutes, and the pH value is adjusted to 6.0-6.2. If the pH value is not within this range, a 0.4-0.6 mol / L sodium hydroxide solution is used for adjustment;

[0056] In step S204, the filter elements are 0.45 μm and 0.22 μm polyethersulfone filter elements, the circulation filtration time is 30-40 minutes, and injection water is supplemented to a total volume of 460-462 kg.

[0057] Specifically, the addition order of niacinamide, mannitol, and vitamin C in step S203 has been optimized. Niacinamide is added first as an auxiliary stabilizer to enhance the antioxidant property of the drug solution. Mannitol is added subsequently as a filler to adjust the osmotic pressure. Vitamin C is added finally to further enhance the antioxidant effect. The synergistic effect of the three significantly improves the stability of the drug solution. The range of the stirring and dissolution time of 8-12 minutes is determined based on the dissolution characteristics of the excipients. Within this time period, the excipients can be completely dissolved and uniformly distributed in the drug solution, avoiding local concentration differences. Adjusting the pH value to 6.0-6.2 is based on the research results of the optimal stability of famotidine within this pH range. If the pH value is too low, it may cause drug degradation, and if it is too high, it may affect the safety of clinical use. The design of the concentration range of using a 0.4-0.6 mol / L sodium hydroxide solution for adjustment considers the influence of adjustment efficiency and the change in the volume of the drug solution. This concentration range can accurately adjust the pH value with a small addition amount, while not significantly diluting the drug solution concentration.

[0058] In step S204, 0.45μm and 0.22μm polyethersulfone filters are used for cyclic filtration. The 0.45μm filter serves as the primary filtration layer to remove larger particulate impurities, and the 0.22μm filter serves as the fine filtration layer to further sterilize and refine particles. This dual-stage filtration design can significantly improve the clarity and sterility of the liquid medicine. The selection of the cyclic filtration time of 30 - 40 minutes is based on the balance between filtration efficiency and filter performance. Too short a time may not completely remove the microparticles, while too long a time may increase the risk of filter clogging or the exposure time of the liquid medicine. The design of adding injection water to a total volume in the range of 460 - 462 kg takes into account the accuracy of the production batch and the minor deviation of the equipment capacity, ensuring that the final concentration of the liquid medicine meets the prescription requirements. After filtration, the liquid medicine is filtered into the storage tank and nitrogen is introduced to maintain a positive pressure. This operation not only prevents external air from entering but also facilitates the subsequent transmission of the liquid medicine in the positive pressure state. The positive pressure controlled within the range of 0.01 - 0.05 MPa has the best effect, being both safe and efficient.

[0059] In step S205, the filters are two 0.22μm polyethersulfone filters, the filtration temperature ≤ 30°C, the filtration time ≤ 10 hours, the pressure difference between the terminal filter and the pipeline ≤ 0.20 MPa, and the bubble point pressure of the filter integrity test ≥ 0.35 MPa.

[0060] Specifically, in step S205, two 0.22μm polyethersulfone filters are used for terminal filtration to further enhance the sterilization effect and ensure the sterile state of the liquid medicine before entering the buffer tank. The polyethersulfone material is selected because of its low protein adsorption and high filtration efficiency. The requirement of the filtration temperature ≤ 30°C aims to avoid the influence of high temperature on the stability of the liquid medicine. Experiments have shown that an increase in temperature may accelerate the oxidation of components such as vitamin C. The design of the filtration time ≤ 10 hours is based on the balance between production efficiency and the storage time of the liquid medicine. Too long a filtration may cause the liquid medicine to stay in the pipeline for too long and degrade. The limit value of the pressure difference between the terminal filter and the pipeline ≤ 0.20 MPa is determined through multiple tests. This range can ensure smooth filtration and avoid overloading and damage of the filter. The bubble point pressure of the filter integrity test ≥ 0.35 MPa is a key indicator to ensure that the filter is intact. The wet filter method is used for detection. If it is lower than this value, it indicates that the filter may have microporous defects and needs to be replaced to ensure the sterilization effect.

[0061] In step S3, the pressure of purified water is 0.25 - 0.50 MPa, the pressure of injection water is 0.10 - 0.30 MPa, the pressure of compressed air is 0.25 - 0.70 MPa, the drying and sterilization temperature of the oven is set at 290 - 310°C, the monitored temperature ≥ 285°C, and the placement time limit after ampoule sterilization does not exceed 1.5 - 2.5 hours.

[0062] Specifically, the pressure ranges of purified water, water for injection, and compressed air in step S3 (0.25 - 0.50 MPa, 0.10 - 0.30 MPa, 0.25 - 0.70 MPa) are designed based on the operating parameters and cleaning effects of the vial washing equipment. Purified water is used for primary washing to remove surface dirt, water for injection is used for fine washing to ensure no residue, and compressed air is used to blow dry the inside of the ampoules. These pressure ranges can ensure thorough cleaning without damaging the ampoules. The oven drying and sterilization temperature is set at 290 - 310 °C. This range can not only effectively kill microorganisms but also quickly dry the ampoules to avoid water residue. The requirement of monitoring the temperature ≥ 285 °C is for real-time verification of the oven performance to ensure consistent sterilization effects. The design of the placement time limit of the sterilized ampoules not exceeding 1.5 - 2.5 hours is based on the need to maintain cleanliness. Exceeding this time may cause microorganisms to reattach to the surface of the ampoules due to environmental pollution, affecting the sterility of subsequent filling.

[0063] In step S4, the filling volume is controlled at 2.15 - 2.23 ml, the target filling volume is 2.18 - 2.20 ml, the residual oxygen rate ≤ 1.0%, the filling speed is 540 - 560 vials per minute, and the first batch of 1200 - 1400 vials of liquid medicine is discarded.

[0064] Specifically, in step S4, the control of the filling volume at 2.15 - 2.23 ml and the target filling volume in the range of 2.18 - 2.20 ml are designed based on the clinical dosage requirements and the accuracy of the filling equipment. This range can ensure that the famotidine content in each ampoule reaches 20 mg, while avoiding overfilling or underfilling. The requirement of the residual oxygen rate ≤ 1.0% is achieved by nitrogen filling. The control of the nitrogen flow rate and the filling environment is the key. When the residual oxygen rate is lower than this value, the oxidation degradation rate of the liquid medicine is significantly reduced. The selection of the filling speed of 540 - 560 vials per minute is based on the performance optimization of the washing, drying, filling, and sealing integrated machine, which not only ensures production efficiency but also avoids filling volume deviation caused by being too fast. The setting of discarding the first batch of 1200 - 1400 vials of liquid medicine takes into account the equipment stability and the uniformity of the liquid medicine at the initial stage of filling. The quality of the liquid medicine at the initial stage may be unstable due to pipeline residues or parameter adjustments not reaching the optimal state. Discarding this part ensures the quality consistency of subsequent products.

[0065] In step S5, the concentration of the carmine solution ≥ 0.2 g / L, and the leak detection conditions are first a negative pressure ≤ -80 kPa maintained for ≥ 8 - 12 minutes, and then a positive pressure ≥ +80 kPa maintained for ≥ 8 - 12 minutes, which can detect leakage apertures of 5 μm and above.

[0066] Specifically, the selection of the carmine solution concentration ≥ 0.2 g / L in step S5 is based on its color development effect and permeability in pressure detection. If the concentration is too low, it may lead to missed detections, and if it is too high, it may remain on the surface of the ampoule and affect the quality. The leak detection conditions are first a negative pressure ≤ -80 kPa maintained for 8 - 12 minutes, and then a positive pressure ≥ +80 kPa maintained for 8 - 12 minutes. This design is optimized through multiple experiments. The negative pressure stage detects whether there are minor leaks inside the ampoule, and the positive pressure stage verifies the sealing strength. This dual detection can effectively identify leak apertures of 5 μm and above, ensuring the integrity of the product during storage and transportation. The setting of the time range of 8 - 12 minutes takes into account the balance between detection sensitivity and production efficiency. If it is too short, it may lead to missed detections, and if it is too long, it will reduce efficiency. In actual operation, it can be fine-tuned to the optimal value according to the equipment performance.

[0067] The specification of famotidine injection is 2 ml:20 mg, the preparation batch quantity is 450 - 470 L, and the packaging form in step S6 is 10 - 14 pieces / box.

[0068] Specifically, the specification of famotidine injection being 2 ml:20 mg is designed based on the commonly used clinical dosage, which can meet the needs of treating diseases related to excessive gastric acid and facilitate precise dosing by doctors. The range of the preparation batch quantity of 450 - 470 L takes into account the volume of the production equipment and the controllability between batches. This batch quantity can meet the requirements of industrial production while ensuring the uniformity and stability of the liquid medicine preparation. The design of the packaging form of 10 - 14 pieces / box in step S6 is based on market demand and transportation convenience. 10 pieces / box is a common specification, but the range of 8 - 12 pieces provides flexibility. The packaging quantity can be adjusted according to different market or customer needs, while ensuring quality control during the packaging process, such as the integrity of the ampoules in each box and the attachment of the instruction manual.

[0069] The storage time limit of the storage tank does not exceed 10 - 12 hours, the storage time limit of the liquid medicine does not exceed 11 - 13 hours, the total production time limit does not exceed 15 - 16 hours, the yield ≥ 87.0%, the microbial load of the liquid medicine before terminal filtration in step S205 ≤ 10 CFU / 100 ml, and the bacterial endotoxin of the filling sample in step S4 < 7.5 EU / mg.

[0070] Specifically, the design of the storage time limits of the liquid storage tank being 10 - 12 hours, the liquid medicine storage time limit being 11 - 13 hours, and the total production time limit being 15 - 16 hours is based on the research of the stability of the liquid medicine and the continuity of the production process. Under nitrogen protection, famotidine injection can maintain chemical and microbial stability within these time ranges. Beyond these ranges, the quality may decline due to oxidation or microbial growth. The index of the finished product rate ≥ 87.0% has been verified through multiple productions, which reflects the high efficiency and stability of this method. The requirement that the microbial load of the liquid medicine before terminal filtration in step S205 is ≤ 10 CFU / 100ml is based on the strict standards of sterile preparations and is achieved through multi-stage filtration and nitrogen protection to ensure that the product meets the requirements of the pharmacopoeia. The limit value of the bacterial endotoxin of the filling sample < 7.5 EU / mg in step S4 is detected by the bacterial endotoxin test method. This index is directly related to the clinical safety of the injection. Being lower than this value can effectively reduce the risk of fever reactions caused by endotoxins.

[0071] The following is an introduction in combination with specific embodiments:

[0072] Example 1: Example of standard parameters

[0073] Step S1 Lactic acid pretreatment

[0074] Weigh 1.58 kg of lactic acid (after purification by weight), dilute it to 9.48 kg with water for injection according to the mass ratio of 1:6, stir evenly and seal it, then perform high-temperature treatment at 120 °C for 180 minutes. The content of lactic acid monomer is detected to be 97.2% (higher than 96.5%). The treated lactic acid solution is stored in a closed container at room temperature for 36 hours for later use.

[0075] Step S2 Liquid medicine preparation

[0076] S201: Add 150% (675 kg) of the preparation amount of water for injection into the concentrated preparation tank, introduce nitrogen, stir at a speed of 60 revolutions per minute, the water temperature is 25 °C, and the dissolved oxygen is 0.8 mg / L.

[0077] S202: Add 70% (315 kg) of the preparation amount of water for injection into the dilute preparation tank, introduce nitrogen, add the pretreated lactic acid solution and the prescription amount corresponding to the 20 mg / 2 ml specification of famotidine (about 4.5 kg), and stir and dissolve for 20 minutes.

[0078] S203: Add nicotinamide, mannitol and vitamin C (according to the prescription amount) in sequence, stir and dissolve for 10 minutes, take a sample to measure the pH value to be 6.1, and no adjustment is required.

[0079] S204: Make up the injection water to the full amount of 460 kg, circulate and filter through 0.45 μm and 0.22 μm polyethersulfone filter elements for 30 minutes, filter into the liquid storage tank, and introduce nitrogen to maintain a positive pressure of 0.03 MPa.

[0080] S205: The liquid medicine in the storage tank is filtered through two 0.22 μm polyethersulfone filter elements and then input into the buffer tank. The filtration temperature is 28 °C, the filtration time is 8 hours, the pressure difference is 0.15 MPa, and the bubble point pressure for the integrity test of the filter element is 0.38 MPa.

[0081] Step S3 Washing the vials

[0082] Wash the ampoules with purified water (pressure 0.40 MPa), injection water (pressure 0.20 MPa), and compressed air (pressure 0.50 MPa). Set the oven temperature at 300 °C, monitor the temperature at 290 °C, and let it stand for 2 hours after sterilization.

[0083] Step S4 Filling

[0084] The liquid medicine is filled by nitrogen injection from the buffer tank. The filling volume is 2.19 ml, the residual oxygen rate is 0.9%, the filling speed is 550 vials per minute, the first batch of 1200 vials of liquid medicine is discarded, the storage time limit of the storage tank is 10 hours, and the total time limit is 14 hours and 30 minutes.

[0085] Step S5 Leak detection

[0086] Use a 0.25 g / L carmine solution. First, maintain a negative pressure of -80 kPa for 10 minutes, then maintain a positive pressure of +80 kPa for 10 minutes to detect leakage pores larger than 5 μm.

[0087] Step S6 Lamp inspection and packaging

[0088] After passing the lamp inspection, it is packaged into boxes of 10 vials each. The finished product rate is 88.5%, the microbial load is 8 CFU / 100 ml, and the bacterial endotoxin is 6.8 EU / mg.

[0089] Example 2: The lowest data example

[0090] Step S1 Lactic acid pretreatment

[0091] Weigh 1.58 kg of lactic acid (after being converted to pure form), dilute it to 9.48 kg with injection water according to a mass ratio of 1:6, stir evenly and seal it, and perform high-temperature treatment at 115 °C for 170 minutes. Detect that the lactic acid monomer content is 96.6% (higher than 96.%), and the treated lactic acid solution is stored airtight at room temperature for 35 hours for standby.

[0092] Step S2 Liquid medicine preparation

[0093] S201: Add injection water at 145% (652.5 kg) of the preparation amount to the concentrated preparation tank, introduce nitrogen, stir at a speed of 58 revolutions per minute, the water temperature is 20 °C, and the dissolved oxygen is 1.0 mg / L.

[0094] S202: Add 65% (292.5 kg) of the formulated amount of water for injection into the dilution tank, introduce nitrogen, add the pretreated lactic acid solution and famotidine (about 4.4 kg), and stir to dissolve for 18 minutes.

[0095] S203: Sequentially add nicotinamide, mannitol, and vitamin C, stir to dissolve for 8 minutes, take a sample to measure the pH value as 5.9, and adjust it to 6.0 with 0.4 mol / L sodium hydroxide solution.

[0096] S204: Make up the water for injection to the full amount of 459 kg, circulate and filter through 0.45 μm and 0.22 μm polyethersulfone filter elements for 25 minutes, filter into the storage tank, and introduce nitrogen to maintain a positive pressure of 0.01 MPa.

[0097] S205: Filter the liquid medicine in the storage tank through two 0.22 μm polyethersulfone filter elements, input it into the buffer tank, the filtration temperature is 25°C, the filtration time is 6 hours, the pressure difference is 0.10 MPa, and the bubble point pressure of the filter element integrity test is 0.35 MPa.

[0098] Step S3 Washing the vials

[0099] Use purified water (pressure 0.25 MPa), water for injection (pressure 0.10 MPa), and compressed air (pressure 0.25 MPa) to wash the ampoules. Set the oven temperature at 290°C, monitor the temperature at 285°C, and place them for 1.5 hours after sterilization.

[0100] Step S4 Filling

[0101] The liquid medicine is filled with nitrogen from the buffer tank, the filling volume is 2.15 ml, the residual oxygen rate is 1.0%, the filling speed is 540 vials per minute, the first batch of 1100 vials of liquid medicine is discarded, the storage time limit of the storage tank is 9 hours, and the total time limit is 14 hours.

[0102] Step S5 Leak detection

[0103] Use 0.20 g / L carmine solution, first maintain a negative pressure of -85 kPa for 8 minutes, then maintain a positive pressure of +80 kPa for 8 minutes, and detect leakage pore diameters above 5 μm.

[0104] Step S6 Lamp inspection and packaging

[0105] After lamp inspection, pack into boxes of 8 vials each, the finished product rate is 87.2%, the microbial load is 10 CFU / 100 ml, and the bacterial endotoxin is 7.2 EU / mg.

[0106] Example 3: Example with the highest data

[0107] Step S1 Pretreatment of lactic acid

[0108] Weigh 1.58 kg of lactic acid (after being converted to pure form), dilute it with water for injection according to a mass ratio of 1:6 to 9.48 kg, stir evenly and seal it, then perform high-temperature treatment at 125 °C for 190 minutes. The content of lactic acid monomer is detected to be 97.8% (higher than 96.5%). The treated lactic acid solution is stored in a sealed container at room temperature for 40 hours for standby use.

[0109] Step S2: Preparation of the liquid medicine

[0110] S201: Add 155% (697.5 kg) of the preparation amount of water for injection into the concentrated preparation tank, introduce nitrogen, stir at a speed of 62 revolutions per minute, the water temperature is 30 °C, and the dissolved oxygen is 0.6 mg / L.

[0111] S202: Add 75% (337.5 kg) of the preparation amount of water for injection into the dilute preparation tank, introduce nitrogen, add the pretreated lactic acid solution and famotidine (about 4.6 kg), and stir and dissolve for 22 minutes.

[0112] S203: Add nicotinamide, mannitol and vitamin C in sequence, stir and dissolve for 12 minutes, take a sample to measure the pH value to be 6.3, and adjust it to 6.2 with 0.6 mol / L sodium hydroxide solution.

[0113] S204: Make up water for injection to the full amount of 461 kg, circulate and filter through 0.45 μm and 0.22 μm polyethersulfone filter elements for 35 minutes, filter into the storage tank, and introduce nitrogen to maintain a positive pressure of 0.05 MPa.

[0114] S205: The liquid medicine in the storage tank is filtered through two 0.22 μm polyethersulfone filter elements and input into the buffer tank. The filtration temperature is 30 °C, the filtration time is 10 hours, the pressure difference is 0.20 MPa, and the bubble point pressure of the filter element integrity test is 0.40 MPa.

[0115] Step S3: Washing the vials

[0116] Use purified water (pressure 0.50 MPa), water for injection (pressure 0.30 MPa) and compressed air (pressure 0.70 MPa) to wash the ampoules. The oven temperature is set at 310 °C, the monitored temperature is 295 °C, and it is placed for 2.5 hours after sterilization.

[0117] Step S4: Filling

[0118] The liquid medicine is filled with nitrogen from the buffer tank, the filling volume is 2.23 ml, the residual oxygen rate is 0.7%, the filling speed is 560 vials per minute, the first batch of 1300 vials of liquid medicine is discarded, the storage time limit of the storage tank is 11 hours, and the total time limit is 15 hours.

[0119] Step S5: Leak detection

[0120] Use a 0.30 g / L carmine solution. First, maintain a negative pressure of -75 kPa for 12 minutes, and then maintain a positive pressure of +85 kPa for 12 minutes to detect leakage hole diameters above 5 μm.

[0121] Step S6 Visual inspection and packaging

[0122] After passing the visual inspection, package them into boxes of 12 pieces each. The finished product rate is 89.0%, the microbial load is 6 CFU / 100 ml, and the bacterial endotoxin is 6.5 EU / mg.

[0123] Example 4: Example with medium-high parameters

[0124] Step S1 Lactic acid pretreatment

[0125] Weigh 1.58 kg of lactic acid (after discounting purity), dilute it to 9.48 kg with water for injection according to a mass ratio of 1:6, stir evenly and seal it, and perform high-temperature treatment at 123 °C for 185 minutes. Detect that the lactic acid monomer content is 97.5% (higher than 96.5%). The treated lactic acid solution is stored sealed at room temperature for 38 hours for later use.

[0126] Step S2 Pharmaceutical solution preparation

[0127] S201: Add water for injection at 152% (684 kg) of the preparation amount to the concentrated preparation tank, introduce nitrogen, stir at a speed of 61 revolutions per minute, the water temperature is 28 °C, and the dissolved oxygen is 0.7 mg / L.

[0128] S202: Add water for injection at 72% (324 kg) of the preparation amount to the dilute preparation tank, introduce nitrogen, add the pretreated lactic acid solution and famotidine (about 4.5 kg), and stir and dissolve for 21 minutes.

[0129] S203: Add nicotinamide, mannitol, and vitamin C in sequence, stir and dissolve for 11 minutes, take a sample to measure the pH value as 6.0, and no adjustment is required.

[0130] S204: Make up water for injection to the full amount of 460.5 kg, circulate and filter through 0.45 μm and 0.22 μm polyethersulfone filters for 32 minutes, filter into the storage tank, and introduce nitrogen to maintain a positive pressure of 0.04 MPa.

[0131] S205: The pharmaceutical solution in the storage tank is filtered through two 0.22 μm polyethersulfone filters and input into the buffer tank. The filtration temperature is 29 °C, the filtration time is 9 hours, the pressure difference is 0.18 MPa, and the bubble point pressure of the filter integrity test is 0.39 MPa.

[0132] Step S3 Bottle washing

[0133] The ampoules are cleaned with purified water (pressure 0.45 MPa), water for injection (pressure 0.25 MPa) and compressed air (pressure 0.60 MPa). The oven temperature is set at 305 °C, the monitored temperature is 292 °C, and it is placed for 2.2 hours after sterilization.

[0134] Step S4 Filling

[0135] The liquid medicine is filled with nitrogen from the buffer tank, the filling volume is 2.20 ml, the residual oxygen rate is 0.8%, the filling speed is 555 pieces / minute, the first batch of 1250 pieces of liquid medicine is discarded, the storage time limit of the liquid storage tank is 10.5 hours, and the total time limit is 14 hours and 45 minutes.

[0136] Step S5 Leak Detection

[0137] Use 0.28 g / L carmine solution, first maintain a negative pressure of -78 kPa for 11 minutes, then maintain a positive pressure of +82 kPa for 11 minutes, and detect leakage hole diameters above 5 μm.

[0138] Step S6 Lamp Inspection and Packaging

[0139] After passing the lamp inspection, it is packaged into 10 pieces / box, the finished product rate is 88.8%, the microbial load is 7 CFU / 100 ml, and the bacterial endotoxin is 6.7 EU / mg.

[0140] Table 1: Comparison of Different Embodiments with the Prior Art Attribute Table

[0141]

[0142]

[0143] Explanation of the meanings of table characters:

[0144] Attribute

[0145] The table column title "Attribute" refers to the key indicators for evaluating the final product quality of the preparation method of famotidine injection. These indicators directly reflect the advantages and disadvantages of the process and the clinical applicability of the product, and are the core basis for comparing the present invention with the prior art.

[0146] Finished Product Rate (%)

[0147] It represents the conversion efficiency from raw materials to the final qualified products during the production process, expressed as a percentage. The calculation formula is: Finished Product Rate = (Number of qualified products after lamp inspection ÷ Theoretical filling quantity) × 100%.

[0148] In this table, the finished product rate reflects the stability of the process and the ability to control losses. The higher the value, the more efficient the process and the less waste. The typical data of the prior art is 85.0%, while the range of the embodiments of the present invention is 87.2% - 89.0%, indicating that this method has improvements in reducing production losses.

[0149] Microbial load (CFU / 100 ml)

[0150] "CFU" stands for "Colony Forming Units", which is a unit for measuring the number of viable bacteria in a liquid medicine; "100 ml" represents the test volume of every 100 milliliters of the liquid medicine.

[0151] Microbial load is an important quality control index for sterile preparations, reflecting the sterilization effect of the process and the ability to ensure sterility. The lower the value, the better the sterility of the liquid medicine. The range of the examples of the present invention is 6 - 10 CFU / 100 ml, which is much lower than the typical data of the prior art ≤20 CFU / 100 ml, showing more stringent microbial control.

[0152] Bacterial endotoxin (EU / mg)

[0153] "EU" stands for "Endotoxin Units", which is a standard unit for measuring the content of bacterial endotoxin; "mg" represents the endotoxin content per milligram of famotidine.

[0154] Bacterial endotoxin is released from the cell wall of Gram-negative bacteria and may cause fever or inflammatory reactions after injection. It is a key indicator of the safety of injection solutions. The lower the value, the safer the product. The typical data of the prior art is <10.0 EU / mg, while the range of the examples of the present invention is 6.5 - 7.2 EU / mg, indicating that the present method is superior in endotoxin control.

[0155] Prior art (typical data)

[0156] The "Prior art" column in the table is based on the typical data of the common production process of famotidine injection solutions, representing the typical results without using the optimized process of the present invention.

[0157] The specific values (such as a yield of 85.0%, microbial load ≤20 CFU / 100 ml, bacterial endotoxin <10.0 EU / mg) are from the industry's conventional level and are used to compare the improvement effect of the present invention. If the actual prior art data is different, it can be replaced to more accurately reflect the advantages.

[0158] Example 1 (standard parameters)

[0159] Indicates the preparation results using standard parameters, that is, the final properties when the process conditions take intermediate values. The yield is 88.5%, the microbial load is 8 CFU / 100 ml, and the bacterial endotoxin is 6.8 EU / mg, representing the stable performance under conventional operations.

[0160] Example 2 (lowest data)

[0161] Indicates the preparation results using the lowest parameters, such as the lowest temperature, time, pressure, etc. The yield is 87.2%, the microbial load is 10 CFU / 100 ml, and the bacterial endotoxin is 7.2 EU / mg, showing that it is still superior to the prior art even under the lowest conditions.

[0162] Example 3 (highest data)

[0163] Indicates the preparation results using the highest parameters, such as the highest temperature, time, pressure, etc. The yield is 89.0%, the microbial load is 6 CFU / 100 ml, and the bacterial endotoxin is 6.5 EU / mg, reflecting the highest quality under the best conditions.

[0164] Example 4 (relatively high in the middle)

[0165] Indicates the preparation results using relatively high middle parameters, balancing efficiency and quality. The yield is 88.8%, the microbial load is 7 CFU / 100 ml, and the bacterial endotoxin is 6.7 EU / mg, which is suitable for the actual production optimization scenario.

[0166] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A preparation method of famotidine injection, characterized in that, It includes the following steps: S1. Lactic acid pretreatment: Weigh lactic acid, dilute it with water for injection and then conduct high-temperature treatment. Detect that the content of lactic acid monomer is not less than 96.5%. The treated lactic acid solution is stored in a sealed manner for standby use. S2. Pharmaceutical solution preparation S201. Add water for injection into the concentrated preparation tank, introduce nitrogen, and start stirring. S202. Add water for injection into the dilute preparation tank, introduce nitrogen, add the lactic acid solution pretreated in step S1 and famotidine, and stir to dissolve. S203. Add nicotinamide, mannitol and vitamin C in sequence, stir to dissolve, take samples for determination and adjust the pH value. S204. Make up water for injection to the full volume. The pharmaceutical solution is filtered through a filter element in a cycle and then filtered into the storage tank, and nitrogen is introduced to maintain positive pressure. S205. The pharmaceutical solution in the storage tank is filtered through a filter element and then input into the buffer tank for standby use. S3. Ampoule washing: Wash the ampoules with filtered purified water, water for injection and compressed air, and then conduct drying and sterilization in an oven. S4. Filling: The pharmaceutical solution is filled under nitrogen from the buffer tank. S5. Leak detection: Use carmine solution for leak detection. S6. Lamp inspection and packaging: After lamp inspection, remove unqualified products and then conduct packaging to obtain the finished product.

2. The preparation method of the famotidine injection according to claim 1, wherein, In step S1, the lactic acid is diluted with water for injection at a mass ratio of 1:

6. The high-temperature treatment conditions are treatment at 115 - 125°C for 170 - 190 minutes. The treated lactic acid solution is stored in a sealed manner at room temperature for no more than 35 - 40 hours.

3. The preparation method of famotidine injection according to claim 1, characterized in that, In step S201, the water for injection is 145 - 155% of the preparation amount. The stirring speed is 58 - 62 revolutions per minute. The water temperature is controlled at 20 - 30°C, and the dissolved oxygen ≤ 1.0 mg / L. In step S202, the water for injection is 65 - 75% of the preparation amount. The stirring and dissolving time of famotidine is 20 - 25 minutes.

4. The preparation method of the famotidine injection according to claim 1, wherein, In step S203, the stirring and dissolving time of nicotinamide, mannitol and vitamin C is 8 - 12 minutes. The pH value is adjusted to 6.0 - 6.

2. If the pH value is not within this range, use 0.4 - 0.6 mol / L sodium hydroxide solution for adjustment. In step S204, the filter elements are 0.45 μm and 0.22 μm polyethersulfone filter elements. The cycle filtration time is 30 - 40 minutes. Make up water for injection to the full volume of 460 - 462 kg.

5. The preparation method of famotidine injection according to claim 1, characterized in that, In step S205, the filter elements are two 0.22 μm polyethersulfone filter elements. The filtration temperature ≤ 30°C, the filtration time ≤ 10 hours, the pressure difference between the terminal filter and the pipeline ≤ 0.20 MPa, and the bubble point pressure of the filter element integrity test ≥ 0.35 MPa.

6. The preparation method of famotidine injection according to claim 1, wherein, In step S3, the pressure of the purified water is 0.25 - 0.50 MPa, the pressure of the water for injection is 0.10 - 0.30 MPa, the pressure of the compressed air is 0.25 - 0.70 MPa. The drying and sterilization temperature of the oven is set at 290 - 310°C, the monitored temperature ≥ 285°C, and the storage time limit of the ampoules after sterilization does not exceed 1.5 - 2.5 hours.

7. The preparation method of the famotidine injection according to claim 1, characterized in that, In step S4, the filling volume is controlled at 2.15 - 2.23 ml, the target filling volume is 2.18 - 2.20 ml, the residual oxygen rate ≤ 1.0%, the filling speed is 540 - 560 vials per minute, and the first 1200 - 1400 vials of the pharmaceutical solution are discarded.

8. The preparation method of the famotidine injection according to claim 1, characterized in that, In step S5, the concentration of the carmine solution is ≥ 0.2 g / L. The leak detection conditions are as follows: first, maintain a negative pressure ≤ -80 kPa for ≥ 8 - 12 minutes, and then maintain a positive pressure ≥ +80 kPa for ≥ 8 - 12 minutes, which can detect leakage apertures of 5 μm and above.

9. The preparation method of famotidine injection according to claim 1, characterized in that, The specification of the famotidine injection is 2 ml: 20 mg, the preparation batch quantity is 450 - 470 L, and the packaging form described in step S6 is 10 - 14 pieces / box.

10. The preparation method of famotidine injection according to claim 1, characterized in that, The storage time limit of the storage tank does not exceed 10 - 12 hours, the storage time limit of the liquid medicine does not exceed 11 - 13 hours, the total production time limit does not exceed 15 - 16 hours, the yield rate ≥ 87.0%. Before terminal filtration in step S205, the microbial load of the liquid medicine is ≤ 10 CFU / 100 ml, and the bacterial endotoxin of the filling sample in step S4 is < 7.5 EU / mg.

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