Production process of ambroxterol oral solution

Abstract

The invention discloses a production process of an ambroxol oral solution, and belongs to the technical field of chemical medicinal preparations, the production process comprises the following steps: adding an aqueous solution containing ambroxol hydrochloride, clenbuterol hydrochloride, sorbitol, propylene glycol, glycerol, hydroxyethyl cellulose, DL-tartaric acid and sodium benzoate into a reaction kettle, and uniformly stirring to obtain the ambroxol hydrochloride oral solution, the clenbuterol hydrochloride, the sorbitol, the propylene glycol, the glycerol, the hydroxyethyl cellulose, the DL-tartaric acid and the sodium benzoate; the preparation method comprises the following steps: preparing in a production system passivated by hydroxyethyl diamine tetraacetic acid trisodium salt, treating by a two-stage series hollow membrane contactor, and finally filling a glass bottle with a liquid medicine. According to the preparation method disclosed by the invention, on the basis of prescription adjustment without adding antioxidants such as sodium pyrosulfite and the like, the impurities of the medicine in the production and storage processes are obviously reduced, the product stability and the clinical medication safety are improved, and the preparation process is simple and stable to operate and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical formulation technology, and in particular to a production process for an ambroxol oral solution. Background Technology

[0002] Ambroxol hydrochloride oral solution is a compound preparation composed of ambroxol hydrochloride and clenbuterol hydrochloride. It is mainly used to treat cough, thick sputum, difficulty in expectoration, and wheezing caused by acute and chronic respiratory diseases (such as acute and chronic bronchitis, bronchial asthma, emphysema, etc.) in children and adults. Among them, ambroxol hydrochloride is a mucolytic agent that can increase the secretion of serous glands in the respiratory mucosa, reduce mucus gland secretion, reduce sputum viscosity, promote the secretion of pulmonary surfactant, and increase bronchial ciliary movement, making sputum easier to cough up. Clenbuterol hydrochloride is a selective β-receptor agonist that relaxes bronchial smooth muscle, enhances ciliary movement, dissolves mucus, and promotes sputum expectoration.

[0003] Since those susceptible to respiratory infections are primarily individuals with weakened immune systems, specific age groups, and those with underlying medical conditions, this product is typically used primarily by children. Furthermore, the drug components in this product exhibit poor stability, particularly ambroxol hydrochloride, which is prone to chemical degradation under conditions such as light, oxidation, high temperatures, and strong alkalis. Therefore, it is necessary to improve the product's stability during preparation and storage through rational formulation and process design, while ensuring product compliance such as taste.

[0004] Ambroxol oral solution was first developed by Boehringer Ingelheim and approved for marketing in Germany in 1984 under the brand name Spasmo-Mucosolvan Saft, in a 100ml strength containing 150mg of ambroxol hydrochloride and 0.1mg of clenbuterol hydrochloride. According to the product instructions and relevant review information, the excipients in this product's formulation are non-crystalline sorbitol solution, glycerin, propylene glycol, hydroxyethyl cellulose, sodium benzoate, DL-tartaric acid, and purified water. However, during production, preparation, and storage, due to the relatively poor chemical stability of ambroxol, and the fact that non-crystalline sorbitol, glycerin, and other excipients in the formulation often contain residual impurities that are difficult to completely remove, as well as their own degradation, the prepared ambroxol solution contains a large amount of impurities, which increase significantly during storage, especially impurity B (…). C 14 H 18 Br2N2O), impurity F ( C 14 H 16 The presence of Br2N2O and other unknown impurities poses a significant threat to the safety of this product in clinical applications, especially in children with weakened immune systems and underdeveloped immune systems.

[0005] Chinese patent document CN 114601793 A discloses an ambroxol oral solution and its preparation method, which involves adding the antioxidant sodium bisulfite to the formula to address the problem of excessively rapid impurity growth. However, sodium bisulfite may cause allergic reactions or asthma attacks in sensitive individuals, and severe allergic reactions may be life-threatening. Furthermore, similar methods of addressing impurity issues by adding antioxidants such as sodium metabisulfite or sodium sulfite have been explicitly rejected by the National Medical Products Administration due to the aforementioned safety risks and are unlikely to be approved.

[0006] Chinese patent document CN 106667902 A discloses a stable ambroxol hydrochloride injection and its preparation method. By adding disodium ethylenediaminetetraacetate and a pH stabilizer, it solves the technical problem of decomposition products being generated under light conditions and increasing with increasing pH value. However, for oral solutions, the need to add excipients such as antibacterial agents and flavoring agents to the prescription may have an adverse effect on the stability of ambroxol hydrochloride.

[0007] Chinese patent document CN 102258462 A discloses a method for improving the stability of ambroxol hydrochloride, pointing out that the presence of glycerin in the formulation has a significant impact on the stability of the active pharmaceutical ingredient, while replacing glycerin with propylene glycol results in a product with good stability. However, replacing all glycerin in the formulation with propylene glycol affects the drug's solubility and potential absorption in the body. Furthermore, adjusting the glycerin content can affect the taste of the oral solution and patient compliance. Similarly, patent document WO2015177147 discloses a substantially glycerin-free and sugar alcohol-free ambroxol hydrochloride cough syrup to improve the stability of ambroxol hydrochloride, while patent document WO2012085185 increases the stability of ambroxol hydrochloride oral solution by removing the antibacterial agent sodium benzoate from the original formulation. The aforementioned patented technology solutions, with significant adjustments to the original formulation, not only fail to meet the requirements for liquid formulations and the drug registration regulations that require the types and amounts of excipients in the original formulation to be basically consistent, but also have a significant potential impact on the product's in vivo absorption or antibacterial properties due to significant changes in the solvent system or the removal of functional components such as antibacterial agents.

[0008] Therefore, there is an urgent need in this field to develop a production process for ambroxol oral solution that ensures low impurities and good storage stability while maintaining consistency with the types and amounts of excipients in the original manufacturer's prescription. Summary of the Invention

[0009] To overcome the shortcomings of the existing technology, the purpose of this application is to provide an ambroxol oral solution, its preparation process and application, so as to meet the requirements of drug registration review, that is, to maintain the same prescription excipients and dosage as the original formulation, and to solve the product quality problems existing in the preparation and storage of the above-mentioned ambroxol oral solution.

[0010] To achieve the above objectives, the present invention adopts the following technical solution:

[0011] One objective of this invention is to provide a manufacturing process for ambroxol oral solution, comprising the following steps:

[0012] S1. Passivation of the production system: First, passivate the preparation and filling production system with a passivation solution. The concentration of trisodium hydroxyethyldiaminetetraacetate in the passivation solution is not less than 5 g / L. Then, discard the passivation solution and clean the entire preparation and filling production system.

[0013] S2. Preparation of the solution: Prepare an ambroxol solution according to the prescribed dosage;

[0014] S3. Hollow membrane contactor treatment and filling: The ambroxol solution that has been circulated and filtered is treated by a two-stage series hollow membrane contactor and then filled into brown soda-lime glass molded pharmaceutical bottles.

[0015] In one embodiment of the present invention, the time for immersion treatment of the passivation solution in the preparation and filling production system is not less than 30 minutes.

[0016] In one embodiment of the present invention, the cleaning solvent of the passivation solution is purified water, and the cleaning is performed until the content of trisodium hydroxyethyldiaminetetraacetate in the rinsing water is below 10 ppm.

[0017] In one embodiment of the present invention, the preparation of the drug solution is as follows: first, the prescribed amount of glycerin and propylene glycol are added to the mixing tank, and hydroxyethyl cellulose is slowly added and dispersed evenly while stirring. Then, half the prescribed amount of purified water is added, heating is turned on and stirring is continued, and then the heating is turned off and non-crystalline sorbitol solution is added. After stirring evenly, sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride are added in sequence and stirred evenly. Then, the remaining purified water is added to make up the volume and stirred evenly. Finally, the prepared ambroxol solution is filtered through a circulation system to obtain the ambroxol solution.

[0018] In one embodiment of the present invention, the heating temperature during the preparation process is 40℃±5℃, and the heating time is not less than 30 minutes; the stirring time after the clenbuterol hydrochloride is added is not less than 10 minutes; the circulating filtration uses a 10μm polypropylene filter bag; the preparation time of the drug solution from the addition of glycerol and propylene glycol to the solution tank to the end of filtration does not exceed 12 hours.

[0019] In one embodiment of the present invention, the membrane material of the hollow membrane contactor is polymethylpentene, and the membrane area is not less than 1.4 m². 2 .

[0020] In one embodiment of the present invention, the purging gas of the hollow membrane contactor is nitrogen, the vacuum pressure is not less than 0.2 MPa, the flow rate of the ammonia bromide solution through the two-stage series hollow membrane contactor does not exceed 15 kg / min, and the time from when the ammonia bromide solution passes through the hollow membrane contactor to when filling is completed does not exceed 6 hours.

[0021] The second objective of this invention is to provide an oral solution of ambroxol prepared by the above method, wherein the oral solution comprises ambroxol hydrochloride, clenbuterol hydrochloride, non-crystalline sorbitol solution, glycerol, propylene glycol, hydroxyethyl cellulose, sodium benzoate, DL-tartaric acid and purified water.

[0022] In one embodiment of the present invention, the ambroxol oral solution is in the form of 100ml: 150mg ambroxol hydrochloride and 0.1mg clenbuterol hydrochloride; the concentration of the non-crystalline sorbitol solution is 175~194mg / ml; the concentration of the glycerol is 128~142mg / ml; the concentration of the propylene glycol is 33~37mg / ml; the concentration of hydroxyethylcellulose is 2.4~2.6mg / ml; the concentration of sodium benzoate is 1.9~2.1mg / ml; and the concentration of DL-tartaric acid is 0.95~1.05mg / ml.

[0023] The above technical solution has the following beneficial effects:

[0024] 1. Using trisodium hydroxyethyldiaminetetraacetate as a metal ion chelating agent can more effectively reduce drug degradation that may be induced by potential metal ion residues on the surface of production equipment, especially iron ion residues. At the same time, the solution preparation system and filling system are effectively cleaned after passivation treatment, avoiding the pediatric drug safety risks that may be introduced by adding additional excipients such as disodium edetate chelating agents in conventional formulations. It also does not change the consistency of the types and amounts of excipients with the reference formulation, thus meeting the regulatory requirements for the registration of liquid formulation drugs.

[0025] 2. A novel approach was developed to process ambroxol oral solution using hollow membrane contactors in series. This not only avoids the large gas and energy consumption associated with conventional nitrogen purging methods that require long-term replacement to control dissolved oxygen levels, but also reduces the dissolved oxygen level in the solution from 2 mg / L under conventional nitrogen purging to below 0.01 mg / L. Furthermore, the unique structure and material characteristics of this contactor effectively dissociate and remove any remaining residual gases or impurities in the solution, significantly reducing further reactions between ambroxol and potential impurities. This effectively controls the impurity level of the prepared solution and improves its storage stability. Detailed Implementation

[0026] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or as per the product instructions. Furthermore, any methods or materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0028] Example 1

[0029] An oral solution of ambroxol, the specific prescription composition of which is shown in Table 1.

[0030] Table 1: Composition of Ambroxol Oral Solution

[0031]

[0032] Its production process includes the following steps:

[0033] S1. Add 199 kg of purified water to the mixing tank, set the stirring speed to 20 rpm, add 1 kg of trisodium hydroxyethyldiaminetetraacetate, and stir for 30 min; open the valve of the mixing tank to allow the passivation solution to pass through the connecting pipeline and the buffer tank and connecting pipeline of the filling and sealing machine, and circulate the passivation solution back to the mixing tank for 30 min; after passivation, treat the trisodium hydroxyethyldiaminetetraacetate solution as waste liquid, and clean the mixing and filling system with purified water;

[0034] S2. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min;

[0035] S3. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 minutes. Then, pass the filtered ambroxol solution through a two-stage series hollow membrane contactor (membrane area 1.4m²) at a rate of 10 kg / min.2 Nitrogen gas is introduced into the contactor as the purging gas, and the vacuum pressure of the contactor is maintained at 0.2 MPa. After treatment, the ammonia bromide solution is immediately filled into glass bottles and sealed.

[0036] Example 2

[0037] The formulation of an ambroxol oral solution is shown in Table 1, and the production process steps are as follows:

[0038] S1. Add 199 kg of purified water to the mixing tank, set the stirring speed to 20 rpm, add 1.5 kg of trisodium hydroxyethyldiaminetetraacetate, and stir for 30 min; open the valve of the mixing tank to allow the passivation solution to pass through the connecting pipeline and the buffer tank and connecting pipeline of the filling and sealing machine, and circulate the passivation solution back to the mixing tank for 30 min; after passivation, treat the trisodium hydroxyethyldiaminetetraacetate solution as waste liquid, and clean the mixing and filling system with purified water;

[0039] S2. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min;

[0040] S3. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 minutes. Then, pass the filtered ambroxol solution through a two-stage series hollow membrane contactor (membrane area 4.0m²) at a rate of 15kg / min. 2 Nitrogen gas is introduced into the contactor as a purging gas, and the vacuum pressure of the contactor is maintained at 0.4 MPa; after treatment, the ammonia bromide solution is immediately filled into glass bottles and sealed.

[0041] Comparative Example 1

[0042] A method for preparing an ambroxol oral solution (conventional preparation process - nitrogen filling) is described in Table 1. The preparation process mainly includes the following steps:

[0043] S1. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min.

[0044] S2. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 minutes.

[0045] S3. Pour nitrogen gas below the liquid level in the mixing tank for at least 1 hour, with a nitrogen pressure of at least 0.1 MPa.

[0046] S4. After nitrogen filling, the ambroxol solution is transported to the filling process, immediately filled into glass bottles, and sealed.

[0047] Comparative Example 2

[0048] A method for preparing an ambroxol oral solution (conventional preparation process - without nitrogen filling) is described in Table 1. The preparation process mainly includes the following steps:

[0049] S1. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min.

[0050] S2. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 minutes.

[0051] S3. After the circulation filtration is completed, the ambroxol solution is transported to the filling process, immediately filled into glass bottles, and sealed.

[0052] Comparative Example 3

[0053] A method for preparing an ambroxol oral solution (patent CN 115137695A formulation and process) involves converting the non-crystalline sorbitol solution into solid sorbitol (129.5 kg) based on its 30% water content, while keeping the other formulation types and amounts unchanged. The preparation process is as follows:

[0054] S1. First, add 60% purified water to completely dissolve hydroxyethyl cellulose and sorbitol. Then, add glycerin, maintain the temperature at 75°C, and stir for 1.5 hours.

[0055] S2. After cooling the solution stirred for 1.5 hours in step S1 to 50°C, add sodium benzoate and tartaric acid in sequence, stir until completely dissolved, then add ambroxol hydrochloride and continue stirring to dissolve.

[0056] S3. Add clenbuterol hydrochloride and propylene glycol, and dilute with water to 1000L to obtain an oral solution.

[0057] Comparative Example 4

[0058] A method for preparing an ambroxol oral solution (patent CN 116327696A, formulation process), the specific formulation composition is shown in Table 2.

[0059] Table 2: Formulation of Ambroxol Oral Solution (Patent CN 116327696A)

[0060]

[0061] Its preparation process mainly includes the following steps:

[0062] S1. Weigh 80% of the prescribed amount of purified water, heat to 40-50℃, add the prescribed amount of ammonia and sodium bicarbonate, and stir to dissolve;

[0063] S2. Add the prescribed amounts of sodium benzoate, glycerin, propylene glycol, and non-crystalline sorbitol solution, and stir to dissolve;

[0064] S3. Add DL-tartaric acid, a pH adjuster, to adjust the pH of the solution;

[0065] S4. Add the prescribed amounts of ambroxol hydrochloride and clenbuterol hydrochloride, and stir to dissolve;

[0066] S5. Add purified water to the total volume;

[0067] S6. Filling and capping;

[0068] S7. Packaging.

[0069] Comparative Example 5

[0070] An ambroxol oral solution (without passivation treatment) is prepared, the formulation of which is shown in Table 1. Its production process mainly includes the following steps:

[0071] S1. Add the prescribed amount of glycerin and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min;

[0072] S2. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 min; then pass the filtered ambroxol solution through a two-stage series hollow membrane contactor (membrane area 1.4m²) at a rate of 10 kg / min. 2 Nitrogen gas is introduced into the contactor as the purging gas, and the vacuum pressure of the contactor is maintained at 0.2 MPa;

[0073] S3. The treated ambroxol solution is immediately filled into glass bottles and sealed.

[0074] Comparative Example 6

[0075] An ambroxol oral solution (passivated with EDTA) has the following specific formulation as shown in Table 1, and its manufacturing process mainly includes the following steps:

[0076] S1. Add 199 kg of purified water to the mixing tank, set the stirring speed to 20 rpm, add 1.5 kg of disodium edetate (EDTA), and stir for 30 min; open the valve of the mixing tank to allow the passivation solution to pass through the connecting pipeline and the buffer tank and connecting pipeline of the filling and sealing machine, and circulate the passivation solution back to the mixing tank for 30 min; after passivation, treat the EDTA solution as waste liquid and clean the mixing and filling system with purified water.

[0077] S2. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min.

[0078] S3. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 min; then pass the filtered ambroxol solution through a two-stage series hollow membrane contactor (membrane area 1.4m²) at a rate of 10 kg / min. 2 Nitrogen gas is introduced into the contactor as a purging gas, and the vacuum pressure of the contactor is maintained at 0.2 MPa; after treatment, the ammonia bromide solution is immediately filled into glass bottles and sealed.

[0079] Comparative Example 7

[0080] The preparation of an ambroxol oral solution (passivated and then nitrogen-purged) has the following formulation as shown in Table 1, and its production process mainly includes the following steps:

[0081] S1. Add 199 kg of purified water to the mixing tank, set the stirring speed to 20 rpm, add 1 kg of trisodium hydroxyethyldiaminetetraacetate, and stir for 30 min; open the valve of the mixing tank to allow the passivation solution to pass through the connecting pipeline and the buffer tank and connecting pipeline of the filling and sealing machine, and circulate the passivation solution back to the mixing tank for 30 min; after passivation, treat the trisodium hydroxyethyldiaminetetraacetate solution as waste liquid, and clean the mixing and filling system with purified water.

[0082] S2. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min.

[0083] S3. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 minutes; purge the solution with nitrogen below the liquid level in the mixing tank for at least 1 hour at a pressure of at least 0.1 MPa; after purging, transfer the ambroxol solution to the filling process, fill it into glass bottles immediately, and seal the bottles.

[0084] Comparative Example 8

[0085] The preparation of an ambroxol oral solution (using only a single-stage contactor) has the following formulation as shown in Table 1, and its production process mainly includes the following steps:

[0086] S1. Add 199 kg of purified water to the mixing tank, set the stirring speed to 20 rpm, add 1 kg of trisodium hydroxyethyldiaminetetraacetate, and stir for 30 min; open the valve of the mixing tank to allow the passivation solution to pass through the connecting pipeline and the buffer tank and connecting pipeline of the filling and sealing machine, and circulate the passivation solution back to the mixing tank for 30 min; after passivation, treat the trisodium hydroxyethyldiaminetetraacetate solution as waste liquid, and clean the mixing and filling system with purified water.

[0087] S2. Add the prescribed amount of glycerol and propylene glycol to the mixing tank, set the stirring speed to 20 rpm, add the prescribed amount of hydroxyethyl cellulose and disperse evenly, then add half of the prescribed amount of purified water, turn on the heating (set the temperature to 40℃) and stir for 30 min; after turning off the heating, add the non-crystalline sorbitol solution, stir for 10 min and disperse evenly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, and continue stirring for 10 min.

[0088] S3. Filter the prepared ambroxol solution through a 10μm polypropylene filter bag for 20 minutes. Pass the filtered ambroxol solution through a single-stage hollow membrane contactor at a rate of 10kg / min. Nitrogen gas is introduced into the contactor as the purging gas, and the vacuum pressure of the contactor is maintained at 0.2MPa. Immediately fill the treated ambroxol solution into glass bottles and seal them.

[0089] Experimental Example 1

[0090] For the chemical stability testing of the active pharmaceutical ingredient (API), since the proportion of clenbuterol in ambroxol hydrochloride oral solution is low (only 0.1 mg) and its chemical properties are relatively stable, and the drug impurities mainly originate from the relatively unstable ambroxol hydrochloride, a forced degradation test was conducted on the ambroxol hydrochloride API under different conditions (strong acid, strong alkali, oxidation, high temperature, and strong light) to examine the chemical stability of ambroxol hydrochloride. The specific test results are shown in Table 3.

[0091]

[0092] Note: ND - Not detected.

[0093] The test results show that ambroxol hydrochloride is relatively stable under strong acid and strong alkali conditions, but it is easily degraded under oxidative, high temperature and light conditions, producing related impurities. The degradation is particularly significant under strong oxygen and strong light conditions, easily producing impurities B, impurity F and other unknown single impurities, indicating that the chemical stability of ambroxol hydrochloride in the product is relatively poor.

[0094] Experimental Example 2

[0095] The compatibility test of raw materials and excipients was conducted using ambroxol hydrochloride, clenbuterol hydrochloride, and aqueous solutions of the two active pharmaceutical ingredients as control groups. Five times the prescribed amount of each excipient (hydroxyethyl cellulose, non-crystalline sorbitol solution, propylene glycol, glycerin, DL-tartaric acid, and purified water) were added, and the compatibility of the raw materials and excipients was investigated under high temperature (60℃) and light (5000 lux) conditions. The test results are shown in Table 4.

[0096]

[0097] The results of this experiment showed that, compared with the control group of ambroxol hydrochloride and clenbuterol hydrochloride, the changes in the content and the status of various impurities in the two active pharmaceutical ingredient compositions were basically the same, indicating that there was no significant interaction between ambroxol hydrochloride and clenbuterol hydrochloride. However, ambroxol hydrochloride is relatively unstable under light conditions and can degrade to produce significant impurities, suggesting that the product should be protected from light during storage. Compared with the control group of ambroxol hydrochloride and clenbuterol hydrochloride compositions, after adding 5 times the prescribed amount of excipients, impurities B, F, and other single impurities increased significantly under both high temperature and light conditions, suggesting that excipients can cause significant chemical degradation of the main component, bromide hydrochloride, under high temperature or strong light conditions.

[0098] Test Example 1

[0099] Determination of dissolved gas content and related substances in solution

[0100] The relevant substances in the sample were determined by high performance liquid chromatography (HPLC). The solvent was water-acetonitrile (50:50). An appropriate amount of the sample was accurately measured and quantitatively diluted with the solvent to prepare a solution containing 0.6 mg of ambroxol hydrochloride per ml. The solution was filtered and the filtrate was collected to obtain the test solution. Simultaneously, accurately measure an appropriate amount of the test solution and quantitatively dilute it with a solvent to prepare a solution containing 1.2 μg of ambroxol hydrochloride per 1 ml, thus obtaining a control solution. The chromatographic conditions are as follows: use octadecylsilane-bonded silica gel as the packing material (YMC Triart C18, 4.6 mm × 150 mm, 3 μm or equivalent column is recommended); use 0.01 mol / L diammonium hydrogen phosphate buffer (adjusted to pH 6.0 with phosphoric acid) as mobile phase A and water-acetonitrile (10:90) as mobile phase B for gradient elution; flow rate is 1.0 ml per minute; column temperature is 30 °C; detection wavelength is 248 nm; injection volume is 20 μl; injector temperature is 5 °C.

[0101] The related substances of the ambroxol oral solution samples prepared in Examples 1-2 and Comparative Examples 1-8 were determined according to the above operating method; at the same time, the oxygen and carbon dioxide contents of the prepared samples were determined using a dissolved oxygen detector and a carbon dioxide analyzer. The test results are shown in Table 5.

[0102]

[0103] Note: ND - Not detected.

[0104] First, based on the measured dissolved oxygen levels, the dissolved oxygen levels of Comparative Examples 2-4 without nitrogen purging or other treatments were approximately 6.5-7.5 mg / L; the dissolved oxygen levels of Comparative Examples 1 and 7 after nitrogen purging were approximately 1.5-1.7 mg / L; the dissolved oxygen level of Comparative Example 8 after single-stage contactor treatment was approximately 0.1 mg / L; and the dissolved oxygen levels of Examples 1-2 and Comparative Examples 5-6 after double-stage series contactor treatment were approximately 0.005 mg / L. This indicates that the hollow contactor used can quickly remove dissolved oxygen from the solution, and the dissolved oxygen level achieved is significantly lower than that achieved by conventional nitrogen purging through displacement. Regarding the dissolved carbon dioxide levels in the solution, the dissolved carbon dioxide levels of Comparative Examples 2-3 without any treatment were... The dissolved carbon dioxide concentration in Comparative Example 4 was approximately 0.8 mg / L, possibly due to the release of dissolved sodium bicarbonate, resulting in a significantly higher concentration (approximately 1.6 mg / L). The carbon dioxide levels in Comparative Examples 1 and 7, treated with nitrogen purging, were essentially the same as in the unpurged cases (approximately 0.7 mg / L). The dissolved carbon dioxide concentration in Comparative Example 8, treated with a single-stage hollow contactor, was approximately 0.3 mg / L. The dissolved carbon dioxide concentrations in Examples 1-2 and Comparative Examples 5-6, treated with two-stage hollow contactors, were approximately 0.005 mg / L. This indicates that conventional nitrogen purging methods have low efficiency in removing carbon dioxide from the solution, while hollow contactors can remove dissolved carbon dioxide gas from the solution with higher efficiency. Therefore, based on the dissolved oxygen and carbon dioxide concentrations in the solution, it is evident that the hollow contactors used can effectively remove dissolved oxygen, carbon dioxide, and other impurities from the solution, with even better removal effects in a two-stage series configuration.

[0105] Secondly, regarding the measured substances in the solutions, the content of impurity B in Comparative Examples 1 and 2 prepared by conventional preparation methods was around 0.2% immediately after production. The content of impurity B was relatively low in the nitrogen-purged solution, suggesting that the dissolved oxygen level in the solution may be conducive to the degradation of impurity B. Compared with Comparative Example 2, the content of impurity B in Comparative Examples 3-4 and 7 was slightly reduced, indicating that in addition to dissolved oxygen level, the formation of impurity B is related to the auxiliary solution, pH, etc. However, the overall improvement was relatively small, accompanied by an increase in other impurity components, especially in Comparative Example 4. Meanwhile, regarding impurity F, the overall content of impurity F in the solutions prepared by different methods was low, all at or below 0.06%, far below the limit of 0.3%.

[0106] Test Example 2

[0107] Determination of elemental impurities

[0108] Accurately weigh an appropriate amount of the test sample and place it in a reaction tube. Accurately measure 100 μl of Au elemental standard solution, 8 ml of nitric acid, and 1 ml of hydrofluoric acid into the same reaction tube, mix well, and pre-digest on a 130℃ hot plate for 40 min. After pre-digestion, remove the reaction tube, allow it to cool to room temperature, cover it with an outer container, and place it in a microwave digester for digestion using the same parameters as above. After digestion, remove the reaction tube and place it on a 130℃ hot plate to remove acid until approximately 1 ml of liquid remains. Remove the reaction tube, allow it to cool to room temperature, and transfer the liquid to a 50 ml volumetric flask. Wash the reaction tube with ultrapure water, collect the washings in the same volumetric flask, dilute to the mark with ultrapure water, and shake well to obtain the test sample solution.

[0109] The elemental impurities in the test solutions of Examples 1-2 and Comparative Examples 1-8 were detected by ICP-MS. The results are shown in Table 6.

[0110]

[0111] Note: ND - Not detected.

[0112] The experimental results showed that trace amounts of nickel, iron, aluminum and other elemental impurities were present in the solutions of Comparative Examples 1-5 that were not passivated. However, Comparative Example 6, which was treated with the conventional chelating agent disodium edetate, could completely eliminate elements such as lead and aluminum, but a small amount of iron remained. In contrast, no related elemental impurities were detected in Examples 1-2 and Comparative Examples 7-8, which were passivated with trisodium hydroxyethyldiaminetetraacetate solution. This indicates that trisodium hydroxyethyldiaminetetraacetate can effectively chelate and remove elemental impurities that may remain on the surface of the equipment.

[0113] Test Example 3

[0114] Stability test

[0115] The ambroxol oral solutions obtained in Examples 1-2 and Comparative Examples 1-8 were placed in glass bottles and subjected to accelerated conditions (temperature 40±2℃, relative humidity 25±5%) to investigate the content and changes of related substances in the prepared samples. The specific experimental results are shown in Table 7 below:

[0116]

[0117] The results of this experimental study show that the ambroxol oral solution prepared in Examples 1 and 2 showed no significant changes in impurities B, F, and total impurities under accelerated conditions, meeting the proposed quality standard requirements and demonstrating good product stability. In Comparative Example 1, impurities B, F, and other single impurities increased rapidly. Although the limits for each impurity were basically met under 3 months of accelerated conditions, the exceedances were relatively severe after 6 months of accelerated conditions. Compared to Comparative Example 1, the increase in impurities in Comparative Example 2 was more significant. Impurity B and other single impurities exceeded the specified limits after 3 months of accelerated conditions, suggesting that the nitrogen purging process can reduce impurity levels to some extent, especially for impurity B and other single impurities. The growth trend of impurities in Comparative Example 3 was similar to that in Comparative Example 1, indicating that the excipients in the formulation affect the generation and growth of impurities, but the problem of exceeding impurity limits still existed under 6 months of accelerated conditions. Comparative Example 4 mainly involved treating purified water with ammonia and sodium bicarbonate, but the impact on impurities was relatively small compared to Comparative Example 1 or Comparative Example 2. Compared to Examples 1-2, although impurities B and F in Comparative Example 5 still increased to some extent during the stabilization process, they both met the specified limits after 6 months of accelerated treatment. However, other single impurities still increased rapidly, exceeding the limit after 6 months of accelerated treatment, suggesting that the solution without passivation treatment may have had its degradation accelerated by residual metal elements. Meanwhile, in Comparative Example 6, where the passivating agent was changed to disodium edetate while maintaining the hollow contact membrane treatment, other single impurities also exceeded the limit after 6 months of accelerated treatment. Combined with the elemental impurity measurement results, this suggests that the degradation of other single impurities may be related to residual iron or aluminum ions in the solution. Compared to Examples 1-2, Comparative Example 7, prepared using nitrogen purging, showed a larger increase in impurities B and F, especially impurity F. Combined with dissolved oxygen detection results, this suggests that high dissolved oxygen conditions may have accelerated the degradation of impurity F. Meanwhile, Comparative Example 8, using only a single-stage contactor, could significantly reduce the growth of impurities such as B, but with prolonged time, impurity B still exceeded the limit after 6 months of accelerated treatment.

[0118] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or terminal device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or terminal device. Unless otherwise specified, an element defined by the phrase "comprising..." or "including..." does not exclude the presence of additional elements in the process, method, article, or terminal device that includes said element. Additionally, in this document, "greater than," "less than," "exceeding," etc., are understood to exclude the stated number; "above," "below," "within," etc., are understood to include the stated number.

[0119] Although the above embodiments have been described, those skilled in the art, once they understand the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the above descriptions are merely embodiments of the present invention and do not limit the scope of patent protection of the present invention. Any equivalent structural or procedural transformations made using the content of the present invention specification, or direct or indirect applications in other related technical fields, are similarly included within the scope of patent protection of the present invention.

Claims

1. A process for the production of ambroxol oral solution, characterized by, The method comprises the following steps: S1. Passivation of the production system: first passivate the preparation and filling production system with a passivation solution, the concentration of which is not less than 5 g / L of trisodium salt of hydroxyethyl diaminetetraacetate, then discard the passivation solution and clean the entire preparation and filling production system; S2. Preparation of the liquid medicine: prepare the ambroxol hydrochloride solution according to the prescription; S3. Hollow membrane contactor treatment and filling: after the ambroxol hydrochloride solution is filtered, it is treated by a double-stage series-connected hollow membrane contactor and then filled into brown soda-lime glass molded medicine bottles.

2. The production process according to claim 1, characterized in that, The time for which the preparation and filling production system is soaked in the passivation solution is not less than 30 minutes.

3. The production process as described in claim 2, characterized in that, The cleaning solvent of the passivation solution is purified water, and the content of trisodium salt of hydroxyethyl diaminetetraacetate in the eluate is less than 10 ppm.

4. The production process according to claim 1, wherein The preparation of the liquid medicine is as follows: first add the prescription amount of glycerol and propylene glycol into a preparation tank, slowly add hydroxyethyl cellulose under stirring to disperse uniformly, then add half of the prescription amount of purified water, start heating and continue stirring, then stop heating, add the non-crystalline sorbitol solution, stir uniformly, then add sodium benzoate, DL-tartaric acid, ambroxol hydrochloride and clenbuterol hydrochloride in sequence, stir uniformly, add the remaining purified water to make up the volume and stir uniformly, and finally filter the prepared ambroxol hydrochloride solution to obtain the ambroxol hydrochloride solution.

5. The production process according to claim 4, characterized in that, The heating temperature in the preparation process is 40℃±5℃, and the heating time is not less than 30 minutes; the stirring time after the addition of the clenbuterol hydrochloride medicine is not less than 10 minutes; and the circulating filtration uses a 10 μm polypropylene filter bag.

6. The production process according to claim 1, wherein The hollow membrane contactor has a membrane material of polymethylpentene, and a membrane area of not less than 1.4 m 2 .

7. The production process according to claim 6, characterized in that, The purging gas of the hollow membrane contactor is nitrogen, the vacuum pressure is not less than 0.2 MPa, and the flow rate of the ambroxol hydrochloride solution through the double-stage series-connected hollow membrane contactor is not more than 15 kg / min.

8. An ambroxol oral solution prepared by the process according to any one of claims 1 to 7, characterized by, The specification of the ambroxol hydrochloride oral solution is 100 ml: ambroxol hydrochloride 150 mg and clenbuterol hydrochloride 0.1 mg, the concentration of the non-crystalline sorbitol solution is 175-194 mg / ml, the concentration of the glycerol is 128-142 mg / ml, the concentration of the propylene glycol is 33-37 mg / ml, the concentration of the hydroxyethyl cellulose is 2.4-2.6 mg / ml, the concentration of the sodium benzoate is 1.9-2.1 mg / ml, the concentration of the DL-tartaric acid is 0.95-1.05 mg / ml, and the pH value of the ambroxol hydrochloride solution should be between 3.5 and 4.5.

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