Preparation process of ambroxterol oral liquid

Abstract

The preparation process of the ambroxoterol oral liquid comprises the following steps: S1, firstly adding purified water into a preparation tank, then adding citric acid and sodium citrate, stirring and dissolving, and adjusting the pH value to 4.5-5.5; s2, sequentially adding methylparaben and propylparaben into the preparation tank, and stirring for dissolving; s3, adding maltitol or erythritol into the preparation tank, and stirring for dissolving; s4, sequentially adding ambroxol hydrochloride and clenbuterol hydrochloride into the preparation tank, and stirring for dissolving; s5, adding ascorbic acid into the preparation tank, and stirring for dissolving; s6, adding essence into the preparation tank, and uniformly stirring; s7, adding the residual purified water into the preparation tank, and fully mixing; nitrogen protection is kept in the whole process of S1-S7; and S8, quickly filling, and sealing by adopting a light-proof container. According to the preparation process of the ambroxol oral liquid, degradation of ambroxol hydrochloride can be effectively reduced, generation of impurities is reduced, the storage stability of the ambroxol oral liquid is improved, and the safety and effectiveness of a product are ensured.

Description

Technical Field

[0001] The invention belongs to the field of medicine preparation, and particularly relates to a preparation process of ambroterol oral solution. Background Art

[0002] Ambroxol oral solution is a compound preparation whose main ingredients are ambroxol hydrochloride and clenbuterol hydrochloride. It is used to treat cough, thick sputum, difficulty in expectoration, wheezing, etc. caused by acute and chronic respiratory diseases (such as acute and chronic bronchitis, bronchial asthma, emphysema, etc.).

[0003] Chinese patent document CN116327696B discloses a stable ambroxol oral solution, wherein the active ingredients are ambroxol hydrochloride and clenbuterol hydrochloride, the stabilizer is ammonia water and sodium bicarbonate, the antibacterial agent is sodium benzoate, the sweetener is sorbitol, the solvent is propylene glycol, glycerol and purified water, and the pH value is 4.0-6.0. The patent points out that although the prior art provides a method for improving the stability of ambroxol hydrochloride injection, the method of adjusting the pH value of the solution alone cannot meet the demand for the stability of the oral solution. Since the oral solution solvent contains propylene glycol and glycerol, and contains flavoring agents and antibacterial agents, the composition is relatively complex, which will cause the impurities in the oral solution to increase, and have an adverse effect on the safety of clinical medication. The incidence of adverse reactions is high, which greatly limits the clinical application prescription of the preparation. Therefore, alkaline substances such as ammonia water and sodium bicarbonate are added as stabilizers in the patent, which suppresses the adverse effects of antibacterial agents, sweeteners and solvents on drug stability, and the impurity growth rate is greatly reduced, which greatly enhances the stability of the preparation.

[0004] Although the above patent attempts to suppress the adverse effects of antibacterial agents, sweeteners and solvents on drug stability by adding ammonia water and sodium bicarbonate as stabilizers, the process still has many deficiencies. Specifically: 1. The use of ammonia water and sodium bicarbonate as stabilizers may have safety and stability issues; 2. The use of sodium benzoate as an antibacterial agent has limitations in antibacterial effect and safety; 3. The large amount of sorbitol, propylene glycol and glycerol used may affect the taste, stability and safety of the preparation; 4. The use of organic acid (DL-tartaric acid) to adjust the pH value may lead to pH instability; 5. No antioxidants are added to the prescription, which cannot effectively prevent the oxidative degradation of the drug.

[0005] Therefore, the present invention provides an improved preparation process of ambroxol oral solution, which optimizes the preparation process of ambroxol oral solution from the aspects of adjusting prescription, improving preparation process, selecting suitable filling process, etc., so that the degradation of ambroxol hydrochloride can be effectively reduced, the generation of impurities can be reduced, the storage stability of ambroxol oral solution can be improved, and the safety and effectiveness of the product can be ensured. Summary of the invention

[0006] Purpose of the invention: In order to overcome the above shortcomings, the purpose of the present invention is to provide a preparation process of ambroxol oral solution, which is reasonably designed, can effectively reduce the degradation of ambroxol hydrochloride, reduce the generation of impurities, improve the storage stability of ambroxol oral solution, ensure the safety and effectiveness of the product, and has broad application prospects.

[0007] The objective of the present invention is achieved through the following technical solutions: A preparation process of ambroxol oral solution comprises the following steps: S1: First add 60%~80% of the process amount of purified water into the preparation tank, then add the process amount of citric acid and sodium citrate into the preparation tank, stir to dissolve, and adjust the pH to 4.5-5.5; S2: sequentially add the process amount of methylparaben and the process amount of propylparaben into the preparation tank, and stir to dissolve; S3: Add the process amount of maltitol or erythritol into the preparation tank and stir to dissolve; S4: adding the process amount of ambroxol hydrochloride and the process amount of clenbuterol hydrochloride into the preparation tank in sequence, stirring and dissolving; S5: adding the process amount of ascorbic acid into the preparation tank, stirring and dissolving; S6: Add the flavor required for the process into the preparation tank and stir evenly; S7: adding the remaining amount of purified water for the process into the preparation tank, mixing thoroughly, and preparing the ambroxol oral solution; maintaining nitrogen protection throughout S1-S7; S8: Fill quickly, use light-proof containers, and seal them.

[0008] The preparation process of the ambroxol oral solution of the present invention adopts a citric acid buffer system to replace the buffer system composed of ammonia water and sodium bicarbonate commonly used in the prior art. The citric acid buffer system has high safety in oral preparations, can effectively maintain the pH value of the solution stable, avoid the degradation of ambroxol hydrochloride by the alkaline environment, and can also avoid the use of ammonia and carbonate compounds, thereby reducing potential safety hazards.

[0009] Ascorbic acid is added as an antioxidant. Ascorbic acid is a safe and effective water-soluble antioxidant that can remove oxidative free radicals in the solution and prevent the oxidative degradation of ambroxol hydrochloride. At the same time, ascorbic acid is well metabolized in the human body and has high safety.

[0010] Purified water is used to replace the common glycerol and propylene glycol in the existing technology (polyol solvents such as glycerol and propylene glycol may interact with the main drug and affect its stability) to reduce the impact of the solvent on the stability of ambroxol hydrochloride.

[0011] Non-reducing sugar alcohols such as maltitol or erythritol are used instead of sorbitol commonly used in the prior art to avoid degradation reactions caused by reducing impurities in sorbitol. Non-reducing sweeteners will not participate in the Maillard reaction, can reduce the formation of impurities, and improve the taste. The preservative uses a combination of methylparaben and propylparaben. This type of preservative is widely used in oral preparations, has a good preservative effect, has little effect on the stability of the main drug, and is used at a low concentration and has high safety.

[0012] The solution is prepared under nitrogen protection throughout the process to reduce the contact between the solution and oxygen, prevent the occurrence of oxidation reactions, and protect the stability of the main drug.

[0013] Optimize the order of addition. That is, prepare the buffer solution first, adjust the pH value before adding the main drug, and finally add the antioxidant (ascorbic acid) and preservative to adjust the pH value first to ensure that the main drug is dissolved in the most stable environment and reduce degradation. At the same time, antioxidants and preservatives may interact with the main drug, and adding them last can reduce this effect.

[0014] Furthermore, in the above-mentioned preparation process of ambroxol oral solution, in S1, the pH is adjusted to 5.0.

[0015] The pH value of the solution was adjusted and stabilized at 5.0, which is the optimal stability range of ambroxol hydrochloride.

[0016] Furthermore, in the above-mentioned preparation process of ambroterol oral solution, the temperature of S1-S7 is controlled at 20-25°C throughout the process.

[0017] High temperature will accelerate the degradation reaction of the main drug. Preparation at 20-25°C can reduce heat-induced degradation and keep the main drug stable.

[0018] Furthermore, in the preparation process of the above-mentioned ambroterol oral solution, the citric acid, maltitol or erythritol, methylparaben, propylparaben, and flavor are all of pharmaceutical grade.

[0019] Impurities in excipients, especially metal ions and reducing substances, may catalyze the degradation of the main drug. The use of high-purity excipients (pharmaceutical grade citric acid, sweeteners and preservatives) can reduce the introduction of impurities and enhance the stability of the preparation.

[0020] Further, the preparation process of the above-mentioned ambroxol oral solution, the filling in S8 specifically comprises the following steps: (1) Preparation: Thoroughly clean the filling equipment, pipelines, and liquid storage tanks according to SOP to remove residues; use 70% isopropyl alcohol as a disinfectant to disinfect the surface of the equipment, and wipe it clean with sterile water after disinfection; sterilize the equipment with wet heat or dry heat to ensure that the equipment is dry and free of moisture; clean the glass bottles and bottle caps to remove dust and impurities; sterilize the bottles and caps with wet heat sterilization or dry heat sterilization; cool the sterilized bottles and caps in a sterile environment for later use; filter the ambroterol oral solution prepared in S7 through a 0.22-μm sterilizing filter membrane; store the filtered solution in a stainless steel liquid storage tank; (2) Inspection before filling: Before filling, check the operating status of the filling machine to ensure that the equipment is normal and the parameters are set correctly; confirm that the infusion pipeline is connected correctly, well sealed and leak-free; check that the nitrogen supply is normal, the purity is not less than 99.9%, and the pressure is stable; replace the nitrogen inside the liquid storage tank and maintain the positive pressure of nitrogen in the tank at 0.02-0.05Mpa; (3) Filling: Before filling each bottle, pre-fill the bottle with nitrogen; fill the filtered ambroxol oral solution into the bottle through a filling machine; after filling, fill the bottle with nitrogen above the liquid surface to form a nitrogen headspace to prevent oxygen residue; (4) Capping and sealing: Capping should be performed immediately after filling; use an automatic capping machine to ensure that the cap is tightened and sealed well; (5) Cleaning and sterilization: Clean the outside of the bottle and then dry it naturally or blow it dry with clean air; sterilize the product surface again through the ultraviolet sterilization channel.

[0021] By optimizing the filling process and combining it with improvements in prescription and preparation technology, the quality of ambroxol oral solution can be comprehensively improved to meet the safety and effectiveness requirements of clinical use and provide patients with reliable drug treatment.

[0022] Furthermore, in the preparation process of the above-mentioned ambroxol oral solution, the filling process parameters in S8 are as follows: the filling temperature is 20-25°C, the filling environment cleanliness is Class D, the nitrogen purity is ≥99.9%, the nitrogen pressure is 0.02-0.05MPa, the filling accuracy is ±0.5%, the capping torque is 2-4 N·m, the storage temperature is 15-25°C, the storage humidity is ≤60%, and the whole process is operated in a dark place.

[0023] Further, the preparation process of the above-mentioned ambroxol oral solution, the material dosage of the above-mentioned preparation process is as follows: 1.5g of ambroxol hydrochloride, 0.001g of clenbuterol hydrochloride, 1.0g of citric acid, 0.5g of sodium citrate, 1.0g of ascorbic acid, 1.0g of methylparaben, 0.2g of propylparaben, 150g of maltitol or erythritol, 0.5g of flavor, and purified water added to 1000mL.

[0024] Compared with the prior art, the present invention has the following beneficial effects: The preparation process of the ambroterol oral solution disclosed in the present invention has a reasonable prescription design, avoids the use of excipients with potential safety hazards, selects safer citric acid buffer systems, preservatives and antioxidants, so that the preparation is more suitable for a wide range of people, reduces the risk of allergies and adverse reactions, uses safe and good-tasting sweeteners and flavors, improves the taste of the oral solution, and increases patient acceptance; by optimizing the pH value, adding suitable antioxidants, reducing excipients that affect the stability of the main drug, and using an inert atmosphere, the stability of the preparation is comprehensively improved, the impurity level is reduced, and the shelf life is extended; the improved process avoids high-temperature operation, simplifies the production process, is suitable for large-scale production, and reduces energy consumption and production costs; by optimizing the filling process, combined with the improvement of the prescription and preparation process, the quality of the ambroterol oral solution can be comprehensively improved. DETAILED DESCRIPTION

[0025] The following examples 1 and 2 are combined with specific experimental data to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention. The following examples 1 and 2 provide a preparation process of an ambroxol oral solution.

[0026] Example 1 The preparation technology of the ambroxol oral solution of embodiment 1 comprises the steps: S1: First, add 70% of the process amount of purified water into the preparation tank, then add the process amount of citric acid and the process amount of sodium citrate into the preparation tank, stir to dissolve, and adjust the pH to 5; S2: sequentially add the process amount of methylparaben and the process amount of propylparaben into the preparation tank, and stir to dissolve; S3: Add the amount of maltitol required for the process into the preparation tank and stir to dissolve; S4: sequentially add the process amount of ambroxol hydrochloride and the process amount of clenbuterol hydrochloride into the preparation tank, and stir to dissolve; S5: Add the process amount of ascorbic acid into the preparation tank and stir to dissolve; S6: Add the strawberry essence required for the process into the preparation tank and stir evenly; S7: Add the remaining amount of purified water used in the process into the preparation tank, mix thoroughly, and prepare the ambroxol oral solution; keep nitrogen protection throughout S1-S7 and control the temperature at 20-25°C; S8: Fill quickly, use light-proof containers, and seal them.

[0027] The filling process of S8 includes the following steps: Step 1: Preparation (1) Equipment cleaning and disinfection Cleaning: Clean filling equipment, pipelines, liquid storage tanks, etc. thoroughly according to SOP to remove residues.

[0028] Disinfection: Use disinfectant (70% isopropyl alcohol) to disinfect the surface of the equipment, and then wipe it clean with sterile water.

[0029] Drying: Sterilize the device with wet heat or dry heat to ensure that the device is dry and free of moisture.

[0030] (2) Preparation of container and lid Cleaning: Clean the glass bottles and bottle caps to remove dust and impurities.

[0031] Sterilization: Sterilize the bottles and caps by moist heat sterilization (121°C, 20 minutes) or dry heat sterilization (250°C, 30 minutes).

[0032] Cooling: The sterilized bottles and caps are cooled in a sterile environment until ready for use.

[0033] (3) Solution preparation Filtration: Filter the prepared ambroxol oral solution through a 0.22 micron sterilizing filter membrane to remove particles and microorganisms.

[0034] Storage: The filtered solution is stored in a stainless steel storage tank, which has stirring and nitrogen protection functions to maintain the uniformity of the solution and prevent oxidation.

[0035] Step 2: Filling operation (1) Inspection before filling Equipment status: Check the operating status of the filling machine to ensure that the equipment is normal and the parameters are set correctly.

[0036] Pipeline connection: Confirm that the infusion pipeline is connected correctly, well sealed, and leak-free.

[0037] Nitrogen system: Check that the nitrogen supply is normal, the purity is not less than 99.9%, and the pressure is stable.

[0038] (2) Nitrogen replacement Liquid storage tank: Turn on nitrogen protection, replace the inside of the liquid storage tank with nitrogen, and maintain a positive nitrogen pressure in the tank (0.02-0.05MPa).

[0039] Filling space: A nitrogen cover is formed around the filler to reduce the oxygen content in the air.

[0040] (3) Filling parameter setting Filling temperature: controlled at room temperature (20-25°C) to avoid high temperature affecting drug stability.

[0041] Filling speed: Set the appropriate filling speed according to the bottle volume and production capacity to ensure production efficiency and avoid foaming or overflow.

[0042] Filling accuracy: Use a high-precision filling pump to control the filling error within ±0.5%.

[0043] (4) Filling process Nitrogen pre-filling: Before filling each bottle, a small amount of nitrogen is used to pre-fill the bottle to remove the air in the bottle.

[0044] Filling operation: The filtered solution is poured into the bottle through a filling machine. During the filling process, the contact area between the solution and the air is minimized to reduce oxidation.

[0045] Nitrogen headspace: After filling, nitrogen is filled above the liquid level in the bottle to form a nitrogen headspace to prevent oxygen from remaining.

[0046] Control liquid level: Fill the volume accurately and leave appropriate liquid head space, usually 5-10% of the bottle volume, to facilitate sealing.

[0047] Step 3: Capping and Sealing (1) Capping operation Cap immediately: Cap immediately after filling to reduce the time the solution is exposed to the air.

[0048] Capping equipment: Use an automatic capping machine to ensure that the cap is tightened and sealed well.

[0049] Capping torque: Set the appropriate capping torque to ensure tightness without damaging the bottle cap, usually 2-4 N·m.

[0050] (2) Sealing inspection Leakage test: Take samples of the sealed products to check the tightness of the bottle caps. A vacuum leakage test can be used.

[0051] Appearance inspection: Check whether the bottle has cracks or damage, and whether the liquid level is consistent.

[0052] Step 4: Cleaning and Sterilization (1) Bottle cleaning External cleaning: After filling and capping, clean the outside of the bottle to remove adherent liquid and dust on the surface. Purified or sterile water can be used to wipe it.

[0053] Drying: Air dry or blow dry with clean air to avoid moisture residue.

[0054] Ultraviolet sterilization: The product surface is sterilized again through the ultraviolet sterilization channel to reduce microbial contamination. Among them, the filling process parameters of S8 are as follows: Filling temperature: 20-25℃ Filling environment cleanliness: Class D (100,000 grade) Nitrogen purity: ≥99.9% Nitrogen pressure: 0.02-0.05MPa Filling accuracy: ±0.5% Capping torque: 2-4 N·m Storage temperature: 15-25℃ Storage humidity: ≤60% The ampicillin oral solution prescription (per liter of solution) of Example 1 is as follows: Ambroxol hydrochloride: 1.5 g Clenbuterol hydrochloride: 0.001 g Citric acid: 1.0 g (to adjust pH) Sodium citrate: 0.5 g (to adjust pH) Ascorbic acid: 1.0 g (antioxidant) Methylparaben: 1.0 g (preservative) Propylparaben: 0.2 g (preservative) Maltitol: 150g (sweetener) Strawberry flavor: 0.5 g Purified water: add to 1000 ml Example 2 The preparation technology of the ampicillin oral solution of embodiment 2 comprises the steps: S1: First, add 70% of the process amount of purified water into the preparation tank, then add the process amount of citric acid and the process amount of sodium citrate into the preparation tank, stir to dissolve, and adjust the pH to 5; S2: sequentially add the process amount of methylparaben and the process amount of propylparaben into the preparation tank, and stir to dissolve; S3: Add the process amount of erythritol into the preparation tank and stir to dissolve; S4: sequentially add the process amount of ambroxol hydrochloride and the process amount of clenbuterol hydrochloride into the preparation tank, and stir to dissolve; S5: Add the process amount of ascorbic acid into the preparation tank and stir to dissolve; S6: Add the strawberry essence required for the process into the preparation tank and stir evenly; S7: Add the remaining amount of purified water used in the process into the preparation tank and mix thoroughly to obtain the ambroxol oral solution; nitrogen protection is maintained throughout S1-S7, and the temperature is controlled at 20-25°C; S8: Fill quickly, use light-proof containers, and seal them.

[0055] Among them, the filling process of S8 is the same as that of Example 1.

[0056] The ampicillin oral solution prescription (per liter of solution) of Example 1 is as follows: Ambroxol hydrochloride: 1.5 g Clenbuterol hydrochloride: 0.001 g Citric acid: 1.0 g (to adjust pH) Sodium citrate: 0.5 g (to adjust pH) Ascorbic acid: 1.0 g (antioxidant) Methylparaben: 1.0 g (preservative) Propylparaben: 0.2 g (preservative) Erythritol: 150g (sweetener) Strawberry flavor: 0.5 g Purified water: add to 1000 ml Effect verification The ambroxol oral solution obtained in Example 1 and Example 2 was subjected to a stability test, as follows: Accelerated test conditions: temperature 40℃±2℃, relative humidity 75%±5%.

[0057] Impurity detection method: Inspection method: Refer to high performance liquid chromatography.

[0058] Specific operations: Solvent: 0.01 mol / L diammonium hydrogen phosphate solution (adjust the pH to 8.0 with phosphoric acid or ammonia water)-acetonitrile (60:40).

[0059] Test solution: Use a cryogenic sample injector to accurately measure 4 ml of the product, place it in a 10 ml volumetric flask, dilute to the mark with solvent, and shake well.

[0060] Control solution: Accurately measure an appropriate amount of the test solution and quantitatively dilute it with solvent to make a solution containing approximately 1.2 μg of ambroxol hydrochloride per 1 ml.

[0061] Sensitivity solution: Accurately measure 5 ml of the control solution, place it in a 20 ml volumetric flask, dilute to the scale with solvent, and shake well.

[0062] System suitability solution: Take an appropriate amount of impurity I reference substance, dissolve it in acetonitrile and dilute it to make a solution containing about 12μg per 1ml. Accurately measure 1ml and place it in a 10ml volumetric flask. Take about 6mg of ambroxol hydrochloride reference substance and place it in the same 10ml volumetric flask. Add solvent to dissolve and dilute to the scale and shake well.

[0063] Chromatographic conditions: Chromatographic column: Agilent ZORBAX Eclipse XDB-C18, 4.6 mm × 150 mm, 5 μm.

[0064] Mobile phase A: 0.01 mol / L diammonium hydrogen phosphate solution (adjust the pH to 8.0 with phosphoric acid or ammonia water)-acetonitrile (85:15).

[0065] Mobile phase B: water-acetonitrile (15:85) Flow rate: 1.0ml / min Detection wavelength: 248nm Column temperature: 35°C Injection volume: 20 μl Autosampler temperature: 5°C Gradient Program: System suitability requirements: In the system suitability solution chromatogram, the separation between the impurity I peak and the ambroxol peak should be greater than 3.0, and the number of theoretical plates based on the ambroxol peak should not be less than 4000. The signal-to-noise ratio of the main component peak height in the sensitivity solution chromatogram should not be less than 10.

[0066] Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0067] Calculation formula: ; ; ; Where: A 特定杂质 is the peak area of ​​a single specific impurity (I, II, III, IV and V) in the chromatogram of the test solution; A 其他单个杂质 It is the peak area of ​​individual impurities except specific impurities (Impurity I, Impurity II, Impurity III, Impurity IV and Impurity V) in the chromatogram of the test solution; A 对照 is the main peak area in the chromatogram of the reference solution; F is the correction factor of specific impurities (impurity I, impurity II, impurity IV, impurity III and impurity V). The correction factors of impurity I, impurity II, impurity IV, impurity III and impurity V are 1.2, 1.0, 1.0, 1.0 and 1.1 respectively.

[0068] Standard limit: If there are impurity peaks in the chromatogram of the test solution, after deducting the excipient peaks before the relative retention time of 0.05 and the clenbuterol peak and excipient peaks between the relative retention time of 0.36 and 0.44, the impurity I and impurity V (relative retention time of about 0.85) calculated by the corrected peak area (multiplied by the correction factors of 1.2 and 1.1 respectively) shall not be greater than the main peak area of ​​the control solution (1.0%), the peak area of ​​impurity II (relative retention time of about 0.82), impurity III (relative retention time of about 1.07) and impurity IV (relative retention time of about 1.12) shall not be greater than 0.2 times (0.2%) of the main peak area of ​​the control solution, the peak area of ​​other single impurities shall not be greater than 0.2 times (0.2%) of the main peak area of ​​the control solution, and the sum of the corrected peak areas of each impurity shall not be greater than 1.5 times (1.5%) of the main peak area of ​​the control solution. Chromatographic peaks that are smaller than the main peak area of ​​the sensitivity solution after correction are ignored (0.05%).

[0069] The stability data results of the ambroxol oral solution of Example 1 and Example 2 are shown in Table 1.

[0070] Table 1 In summary, the present invention provides a preparation process of ambroxol oral solution, which can effectively reduce the degradation of ambroxol hydrochloride, reduce the generation of impurities, improve the storage stability of ambroxol oral solution, and ensure the safety and effectiveness of the product.

[0071] The present invention has many specific application paths, and the above is only a preferred embodiment of the present invention. It should be pointed out that the above embodiments are only used to illustrate the present invention, and are not used to limit the protection scope of the present invention. For those of ordinary skill in the art, several improvements can be made without departing from the principle of the present invention, and these improvements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation process of ambroxol oral solution, characterized in that, The steps include: S1: First add 60%~80% of the process amount of purified water into the preparation tank, then add the process amount of citric acid and sodium citrate into the preparation tank, stir to dissolve, and adjust the pH to 4.5-5.5; S2: sequentially add the process amount of methylparaben and the process amount of propylparaben into the preparation tank, and stir to dissolve; S3: Add the process amount of maltitol or erythritol into the preparation tank and stir to dissolve; S4: sequentially add the process amount of ambroxol hydrochloride and the process amount of clenbuterol hydrochloride into the preparation tank, and stir to dissolve; S5: Add the process amount of ascorbic acid into the preparation tank and stir to dissolve; S6: Add the flavor required for the process into the preparation tank and stir evenly; S7: Add the remaining amount of purified water used in the process into the preparation tank and mix thoroughly to obtain the ambroxol oral solution; maintain nitrogen protection throughout S1-S7 S8: Fill quickly, use light-proof containers, and seal them.

2. The preparation process of the ambroxol oral solution according to claim 1, wherein: In S1, the pH is adjusted to 5.

0.

3. The preparation process of the ampicillin oral solution according to claim 1, wherein: The temperature of S1-S7 is controlled at 20-25°C throughout the process.

4. The preparation process of the ambroxol oral solution according to claim 1, wherein: The citric acid, maltitol or erythritol, methylparaben, propylparaben and flavor are all of pharmaceutical grade.

5. The preparation process of the ampicillin oral solution according to claim 1, characterized in that: The filling in S8 specifically includes the following steps: (1) Preparation: Thoroughly clean the filling equipment, pipelines, and liquid storage tanks according to SOP to remove residues; use 70% isopropyl alcohol as a disinfectant to disinfect the surface of the equipment, and wipe it clean with sterile water after disinfection; sterilize the equipment with wet heat or dry heat to ensure that the equipment is dry and free of moisture; clean the glass bottles and bottle caps to remove dust and impurities; sterilize the bottles and caps with wet heat sterilization or dry heat sterilization; cool the sterilized bottles and caps in a sterile environment for later use; filter the ambroterol oral solution prepared in S7 through a 0.22-μm sterilizing filter membrane; store the filtered solution in a stainless steel liquid storage tank; (2) Inspection before filling: Before filling, check the operating status of the filling machine to ensure that the equipment is normal and the parameters are set correctly; confirm that the infusion pipeline is connected correctly, well sealed and leak-free; check that the nitrogen supply is normal, the purity is not less than 99.9%, and the pressure is stable; replace the nitrogen inside the liquid storage tank and maintain the positive pressure of nitrogen in the tank at 0.02-0.05Mpa; (3) Filling: Before filling each bottle, pre-fill the bottle with nitrogen; fill the filtered ambroxol oral solution into the bottle through a filling machine; after filling, fill the bottle with nitrogen above the liquid surface to form a nitrogen headspace to prevent oxygen residue; (4) Capping and sealing: Capping should be performed immediately after filling; Use an automatic capping machine to ensure that the cap is tightened and sealed well; (5) Cleaning and sterilization: Clean the outside of the bottle and then dry it naturally or blow it dry with clean air; sterilize the product surface again through the ultraviolet sterilization channel.

6. The preparation process of the ampicillin oral solution according to claim 5, characterized in that: The filling process parameters in S8 are as follows: filling temperature is 20-25°C, filling environment cleanliness is Class D, nitrogen purity is ≥99.9%, nitrogen pressure is 0.02-0.05MPa, filling accuracy is ±0.5%, capping torque is 2-4 N·m, storage temperature is 15-25°C, storage humidity is ≤60%, and light-proof operation is performed throughout the process.

7. The preparation process of the ambroxol oral solution according to any one of claims 1 to 6, characterized in that: The material dosage of the above preparation process is as follows: 1.5g of ambroxol hydrochloride, 0.001g of clenbuterol hydrochloride, 1.0g of citric acid, 0.5g of sodium citrate, 1.0g of ascorbic acid, 1.0g of methylparaben, 0.2g of propylparaben, 150g of maltitol or erythritol, 0.5g of flavor, and purified water is added to 1000mL.

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