N-nitrosodimethylamine (NDMA) control technology in ranitidine hydrochloride injection production process

Abstract

The invention provides an N-nitrosodimethylamine (NDMA) control technology in a ranitidine hydrochloride injection production process. The N-nitrosodimethylamine control technology comprises the following steps: step 1; accurately weighing the ranitidine hydrochloride raw material and the activated carbon which are calculated according to the preparation amount; step 2; the preparation method comprises the following steps: adding the raw materials into water for injection which is about 2 / 3 of the total amount, controlling the temperature of the liquid medicine to be 15-20 DEG C in the whole process, stirring to dissolve, adding the water for injection into the solution until the total amount is reached, uniformly stirring, and regulating the pH value to be 6.8-7.5 by using anhydrous disodium hydrogen phosphate; step 3; stirring the raw materials to fully mix the activated carbon with the raw materials; step 4; the raw materials are filtered, and visible foreign matter and bacteria in the raw materials are filtered out; step 5; and treating the ampoule, and filling the treated liquid medicine into the ampoule. In the dissolving and liquid preparation stage, a specific dissolving process is researched and developed, water for injection is quantitatively added for multiple times, and the temperature and the pH value are strictly controlled in a specific range, so that the formation of NDMA is effectively avoided, the solubility and the stability of the medicine are improved, and the risk of adverse reaction is also remarkably reduced.

Description

Technical Field

[0001] The invention relates to the field of ranitidine hydrochloride injection production, and in particular to a technology for controlling N-nitrosodimethylamine (NDMA) in the production process of ranitidine hydrochloride injection. Background Art

[0002] Ranitidine acid injection is an acid suppressant. It is mainly used for: 1. Peptic ulcer bleeding, diffuse gastric mucosal lesion bleeding, anastomotic ulcer bleeding, prevention of rebleeding after gastric surgery, etc.; 2. Acute gastric mucosal damage complicated by stress state, and acute gastric mucosal damage caused by aspirin; it is also commonly used to prevent the occurrence of stress ulcer bleeding under stress state in severe diseases (such as cerebral hemorrhage, severe trauma, etc.); 3. Prevent gastric acid reflux combined with aspiration pneumonia after general anesthesia or major surgery and in patients with weakness and coma.

[0003] Currently, in the production process of ranitidine hydrochloride injection, N-nitrosodimethylamine is difficult to control and often produces a large amount of N-nitrosodimethylamine, rendering the finished product unusable. Summary of the invention

[0004] To solve the above problems, the present invention proposes a N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection to solve the above problems in the prior art.

[0005] To achieve the above object, the present invention provides a technology for controlling N-nitrosodimethylamine (NDMA) in the production process of ranitidine hydrochloride injection, comprising the steps of:

[0006] Step 1: Accurately weigh the ranitidine hydrochloride raw material and activated carbon calculated according to the preparation amount;

[0007] Step 2: Add about 2 / 3 of the total amount of water for injection, control the temperature of the liquid medicine at 15-20°C during the whole process, stir to dissolve, add water for injection to the full amount of the solution, stir evenly, and adjust the pH value to 6.8-7.5 with anhydrous disodium hydrogen phosphate;

[0008] Step 3: Stir the raw materials to fully mix the activated carbon with the raw materials;

[0009] Step 4: Filter the raw materials to remove visible foreign matter and bacteria in the raw materials;

[0010] Step 5: Treat the ampoule and fill the treated liquid medicine into the ampoule.

[0011] Furthermore, the raw material is stirred for 20 minutes, and activated carbon is continuously added during stirring.

[0012] Furthermore, the stirred liquid was filtered for the first time using a plate and frame filter sandwiching two layers of medium-speed filter paper and a mixed cellulose ester microporous filter membrane with a pore size of 0.22 um.

[0013] Furthermore, the drug solution that has passed the first filtration is finely filtered using a polypropylene microporous filter rod with a pore size of 0.22 μm, and finally sterilized and filtered through a polyethersulfone microporous filter rod with a pore size of 0.22 μm. The filtered drug solution is checked for visible foreign matter and has a pH value of 6.8-7.5.

[0014] Furthermore, the filling liquid enters the filling storage tank through aseptic double filtration, and then enters the filling machine to pour the liquid medicine (2.25ml) into the ampoule, and then the nitrogen filling pressure is maintained at 0.001-0.002MPa (or until the foam of the liquid medicine in the ampoule is slightly blown and there is no burnt head after it is melted and sealed), and then filled with nitrogen, and then melted and sealed.

[0015] Furthermore, the ampoule is washed and dried before being filled with the liquid medicine.

[0016] Furthermore, the drying procedure of the ampoule is as follows: the ampoule is injected with circulating water (35-60°C) - ultrasonic oscillation → inverted with the mouth facing downward, rinse the inner and outer walls of the bottle with circulating water - rinse the inner wall of the bottle with circulating water - blow the circulating water in the bottle with compressed air - rinse the inner wall of the bottle with injection water → blow the water inside and outside the bottle with compressed air - blow the water in the bottle with compressed air - preheat - high temperature sterilization to remove pyrogens → cool.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] 1. During the dissolution and preparation stage, a specific dissolution process was developed, water for injection was added quantitatively multiple times, and the temperature and pH value were strictly controlled within a specific range, which effectively avoided the formation of NDMA, not only improved the solubility and stability of the drug, but also significantly reduced the risk of adverse reactions;

[0019] Second, inert gas nitrogen is used to replace oxygen during the preparation and filling process, and the possibility of oxidation reaction is greatly reduced by controlling the nitrogen concentration and pressure within the optimal range, thereby effectively preventing the oxidation of raw materials during the production process and avoiding the formation of NDMA;

[0020] 3. By screening filters of different materials and pore sizes, combined with optimized filtration processes and parameters, we can achieve deep removal of tiny particles and harmful impurities in the solution, while avoiding the introduction of NDMA contamination. This innovation ensures the high purity and safety of the drug;

[0021] The use of tunnel ovens for high-temperature drying and sterilization replaces the traditional infrared drying oven, which not only improves the drying and sterilization effects of ampoules but also improves production efficiency. At the same time, the nitrogen filling pressure of the ampoules is maintained at 0.001-0.002MPa to avoid product oxidation to produce NDMA or introduce pollution sources, and effectively extend the shelf life of the product.

[0022] For better understanding and implementation, the present invention is described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a schematic diagram of the overall process of the present invention. DETAILED DESCRIPTION

[0024] In order to have a clearer understanding of the technical features, purposes and effects of the present invention, specific implementation methods of the present invention are now described with reference to the accompanying drawings, but the protection scope of the present invention is not limited to the following.

[0025] refer to Figure 1 As shown, a technology for controlling N-nitrosodimethylamine (NDMA) in the production process of ranitidine hydrochloride injection includes: (1) accurately weighing the ranitidine hydrochloride raw material and activated carbon calculated according to the preparation amount. Adding them to about 2 / 3 of the total amount of water for injection, the temperature of the liquid medicine is controlled at 15-20°C during the whole process, stirring to dissolve. Adding water for injection to the solution to the full amount, stirring evenly, and adjusting the pH value to 6.8-7.5 with anhydrous disodium hydrogen phosphate.

[0026] (2) Add activated carbon and stir evenly for 20 minutes. Then use a plate-and-frame filter to filter with two layers of medium-speed filter paper and a mixed cellulose ester microporous filter membrane with a pore size of 0.22 μm, and then use a polypropylene microporous filter rod with a pore size of 0.22 μm for fine filtration. Finally, use a polyethersulfone microporous filter rod with a pore size of 0.22 μm for sterilization filtration. Check the filtered liquid for visible foreign matter and the pH value should be 6.8-7.5.

[0027] (3) Select ampoules of qualified quality and wash and dry them according to the procedure. The washing and drying procedure of ampoules is as follows: inject circulating water (35-60℃) into the ampoule, ultrasonic oscillate, invert with the mouth facing downward, rinse the inner and outer walls of the bottle with circulating water, rinse the inner wall of the bottle with circulating water, blow out the circulating water in the bottle with compressed air, rinse the inner wall of the bottle with injection water, blow out the water inside and outside the bottle with compressed air, blow out the water in the bottle with compressed air, preheat, sterilize at high temperature to remove pyrogens, and cool.

[0028] (4) Under the pressure of nitrogen, the drug liquid passes through a sterile double filter and enters the filling and sealing drug storage tank, and then enters the filling and sealing machine to pour the drug liquid (2.25 ml) into the ampoule. The nitrogen filling pressure is maintained at 0.001-0.002 MPa (or until the foam of the drug liquid in the ampoule is melted and sealed by slightly blowing). After filling with nitrogen, it is melted and sealed.

[0029] The present invention provides a technical solution that develops a specific dissolution process during the dissolution and liquid preparation stage, adds injection water in a quantitative manner multiple times, and strictly controls the temperature and pH value within a specific range, thereby effectively avoiding the formation of NDMA, which not only improves the solubility and stability of the drug, but also significantly reduces the risk of adverse reactions.

[0030] Secondly, inert gas nitrogen is used to replace oxygen during the liquid preparation and filling process, and by controlling the nitrogen concentration and pressure within the optimal range, the possibility of oxidation reactions is greatly reduced, thereby effectively preventing the oxidation of raw materials during the production process and avoiding the formation of NDMA.

[0031] In the filtration process stage, we developed efficient filtration technology. By screening filters of different materials and pore sizes, combined with optimized filtration processes and parameters, we achieved deep removal of tiny particles and harmful impurities in the solution, while avoiding the introduction of NDMA contamination. This innovation ensures the high purity and safety of the drug.

[0032] During the research stage of the filling and sealing process, the ampoule processing procedure was optimized and compressed air was used for cleaning inside the bottle. In addition, a tunnel oven was used for high-temperature drying and sterilization, replacing the traditional infrared drying oven. This not only improved the drying and sterilization effects of the ampoule, but also improved production efficiency. At the same time, the nitrogen filling pressure of the ampoule was maintained at 0.001-0.002MPa to avoid product oxidation to produce NDMA or introduce pollution sources, and effectively extend the shelf life of the product.

[0033] The above disclosure is only the preferred embodiment of the present invention, which certainly cannot be used to limit the scope of the present invention. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope covered by the present invention.

Claims

1. A technology for controlling N-nitrosodimethylamine (NDMA) in the production process of ranitidine hydrochloride injection, characterized in that: The steps include: Step 1: Accurately weigh the ranitidine hydrochloride raw material and activated carbon calculated according to the preparation amount; Step 2: Add about 2 / 3 of the total amount of water for injection, control the temperature of the liquid medicine at 15-20°C during the whole process, stir to dissolve, add water for injection to the full amount of the solution, stir evenly, and adjust the pH value to 6.8-7.5 with anhydrous disodium hydrogen phosphate; Step 3: Stir the raw materials to fully mix the activated carbon with the raw materials; Step 4: Filter the raw materials to remove visible foreign matter and bacteria in the raw materials; Step 5: Treat the ampoule and fill the treated liquid medicine into the ampoule.

2. The N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection according to claim 1, characterized in that: The raw materials were stirred for 20 minutes, and activated carbon was continuously added during stirring.

3. The N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection according to claim 1, characterized in that: The stirred solution was filtered for the first time using a plate and frame filter with two layers of medium-speed filter paper and a mixed cellulose ester microporous filter membrane with a pore size of 0.22 μm.

4. The N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection according to claim 3, characterized in that: Use a polypropylene microporous filter rod with a pore size of 0.22μm to finely filter the drug solution that has passed the first filtration, and finally filter it through a polyethersulfone microporous filter rod with a pore size of 0.22μm for sterilization. Check the filtered drug solution for visible foreign matter and the pH value should be 6.8-7.

5.

5. The N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection according to claim 1, characterized in that: The filling liquid enters the filling storage tank through aseptic double filtration, and then enters the filling machine to pour the liquid medicine (2.25ml) into the ampoule. The nitrogen filling pressure is maintained at 0.001-0.002MPa (or until the foam of the liquid medicine in the ampoule is melted and sealed without burnt head after slightly blowing). After filling with nitrogen, it is melted and sealed.

6. The N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection according to claim 1, characterized in that: Before filling the ampoule with liquid medicine, wash and dry the ampoule.

7. The N-nitrosodimethylamine (NDMA) control technology in the production process of ranitidine hydrochloride injection according to claim 6, characterized in that: The drying procedure of the ampoule is as follows: the ampoule is filled with circulating water (35-60° C.) and ultrasonically vibrated, the ampoule is inverted with the mouth facing downward, the inner and outer walls of the bottle are rinsed with circulating water, the inner wall of the bottle is rinsed with circulating water, the circulating water in the bottle is blown clean with compressed air, the inner wall of the bottle is rinsed with injection water, the water inside and outside the bottle is blown clean with compressed air, the water in the bottle is blown clean with compressed air, the preheating is carried out, the high temperature sterilization is carried out to remove pyrogens, and the cooling is carried out.

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