A preparation method of acetaminophen oral solution

Abstract

The invention discloses a method for preparing an oral solution of acetaminophen, which specifically comprises the following steps: adding water to a batching tank and starting stirring, dissolving sodium citrate, sodium benzoate and sodium saccharin in water and adding them to the batching tank, then heating and dissolving butylated hydroxyanisole and propylene glycol and adding them to the batching tank, then adding polyethylene glycol 1500, sorbitol, glycerol and citric acid, heating and boiling, keeping warm and stirring for 30 minutes, then cooling to 55°C, adding acetaminophen, stirring for 20 minutes to dissolve, then cooling to below 40°C, dissolving lemon yellow, allure red and banana flavor in water and mixing them, then adding them to the batching tank, then settling to 1000mL with pure water, stirring for 10 minutes, filtering, filling, screwing on the cap, sealing and packaging to obtain a finished product. The present invention adopts a thermal conductive filler to ensure the temperature stability of the liquid medicine during the batching process, and also adopts polyethersulfone and polyamide to prepare a filter membrane, and controls the uniform formation of pores by additives to ensure the filtration efficiency, thereby comprehensively improving the product quality.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and more specifically, relates to a method for preparing an acetaminophen oral solution. Background Art

[0002] Paracetamol, also known as acetaminophen, is also known as Tylenol, Panadol, and Bufferin. It is a non-anti-inflammatory antipyretic analgesic commonly used in clinical practice. It selectively inhibits the synthesis of prostaglandins in the hypothalamic temperature regulation center by inhibiting cyclooxygenase, leading to peripheral vasodilation and sweating to achieve the antipyretic effect. Its antipyretic effect is similar to that of aspirin, but its analgesic effect is weaker. It has the characteristics of rapid and complete oral absorption, low toxicity and side effects, and safe use. It is especially suitable for children and diseases that are allergic to, intolerant of, or not suitable for the use of aspirin, such as chickenpox, hemophilia, peptic ulcers, and gastritis. It has a fast antipyretic speed and good effect. It is often used clinically to quickly relieve children's high fever.

[0003] At present, there are many acetaminophen products in the domestic pharmaceutical market, including tablets, capsules, drops, enemas and oral liquids, among which acetaminophen oral liquid is the most commonly used antipyretic drug for children in clinical practice. There are two problems in the existing preparation process of acetaminophen oral liquid: first, the raw materials need to be heated appropriately in the batching tank, but the raw materials (solubility, stability) are sensitive to temperature, so the heating temperature needs to be strictly controlled and the temperature stability needs to be maintained; second, the oral solution needs to be filtered and impurities removed after volume is fixed, but the filtering effect of the existing filter is not enough, which affects the quality of the product.

[0004] In summary, how to provide a method for preparing acetaminophen oral solution, by controlling the temperature stability during the batching process and improving the product filtration efficiency, and comprehensively improving the product quality, is a problem that urgently needs to be solved. Summary of the invention

[0005] The purpose of the present invention is to solve the above technical problems and provide a method for preparing an acetaminophen oral solution, which ensures the temperature stability of the drug solution by using a heat-conductive filler in the batching process, and also adopts a filter membrane prepared by a composite of polyethersulfone and polyamide, and controls the uniform formation of pores through additives to ensure the filtration efficiency of the filter membrane, thereby comprehensively improving the product quality.

[0006] The present invention achieves the above-mentioned purpose through the following technical solutions:

[0007] A preparation method of paracetamol oral solution specifically comprises the following steps: adding 500 ml of water to a mixing tank and starting stirring, dissolving sodium citrate, sodium benzoate and sodium saccharin in water and adding the solution to the mixing tank, then heating and dissolving butylated hydroxyanisole and propylene glycol and adding the solution to the mixing tank, then adding polyethylene glycol 1500, sorbitol, glycerol and citric acid, heating and boiling, keeping the temperature and stirring for 30 minutes, then cooling to 55°C, adding paracetamol, stirring for 20 minutes to dissolve, then cooling to below 40°C, dissolving lemon yellow, allura red and banana essence in water and mixing the solution, then adding the solution to the mixing tank, then making the volume to 1000 ml with pure water, stirring for 10 minutes, filtering, filling, capping, sealing and packaging to obtain a finished product.

[0008] The batching tank is filled with a thermal conductive filler, and the amount of the thermal conductive filler added is 5-10% of all materials. The preparation method is as follows:

[0009] (1) Add a mixture of allyl polyoxyethylene ether (APEG350, 400 or 500) and an organic peroxide initiator dropwise into styrene and react at 70-90°C for 3-5 hours to obtain a compatibilizer;

[0010] (2) The porous metal fiber and the sodium bicarbonate powder are dispersed for 30 to 60 minutes, and then mixed with the molten polypropylene resin and the compatibilizer, and then injection molded at 170 to 180° C. to obtain the initial filler;

[0011] (3) Spray the surface of the initial filler with aluminum chloride solution, let it stand for 30 to 40 minutes, then clean the filler surface with deionized water, and then heat it at 145 to 155°C for 30 to 50 minutes, then spray the sealing agent, heat (60 to 100°C) and bake for 1 to 3 hours, and then wash the filler surface with acetic acid solution (8-15%) and deionized water in turn. After drying, the thermal conductive filler is obtained.

[0012] Furthermore, the acetaminophen oral solution is prepared from the following raw materials: 24-32 g of acetaminophen, 150-250 g of sorbitol, 200-300 g of glycerol, 150-250 g of polyethylene glycol 1500, 2-8 g of propylene glycol, 0.01-0.04 g of butylated hydroxyanisole, 3-9 g of citric acid, 2-6 g of sodium citrate, 2-8 g of saccharin sodium, 1-5 g of sodium benzoate, 1-5 g of banana flavor, 0.001-0.03 g of allura red, 0.005-0.025 g of tartrazine, and the volume is made up to 1000 mL with purified water.

[0013] Furthermore, in step (1), the molar ratio of styrene to allyl polyoxyethylene ether is 1:(0.8-1.2), the organic peroxide initiator is di-tert-butyl peroxide, diisopropyl peroxydicarbonate or benzoyl peroxide, and the addition amount thereof is 2-4%; in step (2), the mass ratio of porous metal fiber, polypropylene resin and compatibilizer is (0.1-0.4):1:(0.03-0.08), and the mass ratio of porous metal fiber to sodium bicarbonate powder is 1: (0.05-0.1), the material of the porous metal fiber is specifically copper, aluminum, zinc, iron or steel; in step (3), the mass concentration of the aluminum chloride solution is 20-30%, and the amount thereof sprayed is 15-25 times the mass of the sodium bicarbonate powder, and the mass ratio of the sealing agent to the initial filler is (0.06-0.1): 1, the sealing agent is an air-dried phenolic resin, and its specific composition is: 50-70% phenolic resin, 10-20% anhydrous ethanol, and 20-30% toluene.

[0014] The shape of the thermal conductive filler can be sheet-shaped, ring-shaped or cylindrical, with an average diameter of 0.5 to 5 cm. The thermal conductive filler can be filtered and recycled before being fixed to volume with pure water.

[0015] The present invention also provides a filter membrane used in a method for preparing an acetaminophen oral solution, wherein the solution is filtered using a filter membrane having a pore size of 0.4 to 0.5 μm after being fixed to volume with pure water. The method for preparing the filter membrane comprises the following steps:

[0016] The polyethersulfone, polyamide and N,N-dimethylacetamide are mixed evenly, and then polyethylene glycol 400 or 600 and additives are added, and stirred evenly at 40-60°C to obtain a transparent casting liquid. After degassing and filtration, the casting liquid is cast on a glass plate at room temperature to form a film, and the film is allowed to stand in the air for 20-40 minutes, and then the glass plate is immersed in a coagulation bath (0.2% N,N-dimethylacetamide solution) for 10-30 seconds to solidify into a film, and then immersed in deionized water for 1-3 days, and dried to obtain the filter membrane.

[0017] Furthermore, the mass ratio of the polyethersulfone, polyamide, N,N-dimethylacetamide, polyethylene glycol 400 or 600, and the additive is 1: (0.3-0.6): (1-4): (2-3): (0.12-0.26).

[0018] Furthermore, the preparation method of the additive is:

[0019] S1. Mix 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone evenly, add a redox initiator dropwise at 60-80° C. and stir for 2-5 hours to obtain a copolymer;

[0020] S2. Evenly mix the copolymer and polyethylene glycol 600 or 800, then drop the catalyst at 90-110° C., and stir to react for 3-6 hours to obtain the additive.

[0021] Furthermore, the molar ratio of polyethylene glycol 600 or 800, 3,4-epoxy-1-butene, styrene, and N-vinyl pyrrolidone is 1:(1.4-2):(1-1.5):(1-1.6); in step S1, the redox initiator is benzoyl peroxide / N,N-dimethylaniline, hydrogen peroxide / tartaric acid or persulfate / thiol, and the addition amount thereof is 1.5-3%; in step S2, the catalyst is boron trifluoride etherate or aluminum trichloride etherate.

[0022] The present invention also provides a preliminary impurity removal method in the preparation method of acetaminophen oral solution, which includes preliminary impurity removal of the obtained medicinal solution before filtering after the volume is fixed with pure water. The preliminary impurity removal method is: after the obtained medicinal solution is kept warm at 26-30°C for 4-10 hours, the keeping warm is stopped, and 5-10% of an impurity remover is added and stirred for 1-3 hours.

[0023] Furthermore, the preparation method of the impurity remover comprises the following steps:

[0024] A. Mix heptadecane and dodecanol at 30-40°C, then add dextrin and water, stir evenly and make into 5-20 mesh granules by granulator for later use;

[0025] B. Prepare polyvinyl acetal diethylamine acetate (AEA) into a 5-7% ethanol solution, then add molecular sieves and mix evenly, then spray evenly onto the surface of the particles obtained in step A, and then dry to obtain an impurity remover, wherein the impurity remover is stored at 15-18°C for more than 2 hours before use.

[0026] Furthermore, in step A, the mass ratio of heptadecane to dodecanol is 1:(0.5-4), the mass ratio of dextrin to water is 1:(1-3), and the total amount of dextrin and water added is 3-6% of the total amount of heptadecane and dodecanol; in step B, the mass ratio of the solution to the molecular sieve is 1:(0.4-0.6), and the injection amount is 4-10% of the particles.

[0027] The beneficial effects of the present invention are:

[0028] (1) In the process of preparing the acetaminophen oral solution, the present invention uses a thermally conductive filler to enhance the heat transfer of the material, avoid the situation where the material is heated unevenly inside and thus deteriorates, and promote the stability of the oral solution and the dissolution effect of acetaminophen.

[0029] (2) The thermal conductive filler of the present invention is mainly composed of polypropylene resin, and porous metal fibers are added for thermal conductivity. At the same time, a compatibilizer synthesized from styrene and allyl polyoxyethylene ether is used to improve the compatibility between the polypropylene resin and the metal.

[0030] (3) When preparing the thermally conductive filler, the present invention also introduces sodium bicarbonate powder into the pores of the porous metal fiber. Then, during the polypropylene injection molding process, the sodium bicarbonate decomposes to form pores in the filler, and the pores are formed on the surface of the metal fiber. Then, aluminum chloride is sprayed into the pores and heated to form active alumina in the pores. Then, a sealing agent is used to stably store the active alumina in the pores. Therefore, the thermally conductive filler of the present invention can rapidly transfer heat through the active alumina and the metal fiber in sequence, and has good thermal conductivity.

[0031] (4) The present invention adopts a filtration membrane prepared by a composite of polyethersulfone (non-polar) and polyamide (polar), which can comprehensively improve the filtration effect of the filtration membrane.

[0032] (5) When preparing the filtration membrane of the present invention, the additives used are respectively prepared by reacting polyethylene glycol, 3,4-epoxy-1-butene, styrene, and N-vinyl pyrrolidone, which can not only improve the compatibility of the system with the porogen polyethylene glycol and promote the uniformity of pores, but also improve the mixing effect of polyether sulfone and polyamide, thereby further improving the filtration efficiency.

[0033] (6) The addition of the thermally conductive filler makes the liquid medicine heated evenly, which promotes the dissolution of acetaminophen and the dissolution of insoluble impurities. The dissolved part of the insoluble impurities is unstable and easy to cool and precipitate in the subsequent process, which not only easily blocks the pores of the filter membrane, but also reduces the purity of the liquid medicine. Therefore, the present invention also performs preliminary impurity removal on the liquid medicine before filtering after the pure water is fixed to volume to remove the dissolved part of the insoluble impurities.

[0034] The impurity remover used in the preliminary impurity removal process is granulated with phase change materials heptadecane and dodecanol as the main materials, and then sprayed with a mixture of water-insoluble materials and molecular sieves for coating. The phase change temperature of the prepared impurity remover is in the range of 22-24°C. After cooling, it is added to a liquid medicine kept at 26-30°C, which can absorb heat to reduce the temperature of the liquid medicine around the impurity remover, thereby precipitating impurities and adsorbing them in the molecular sieve to achieve the purpose of impurity removal. DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Example 1

[0037] The present embodiment provides an acetaminophen oral solution, the preparation raw materials of which are: acetaminophen 24g, sorbitol 150g, glycerol 200g, polyethylene glycol 1500 150g, propylene glycol 2g, butylated hydroxyanisole 0.01g, citric acid 3g, sodium citrate 2g, saccharin sodium 2g, sodium benzoate 1g, banana flavor 1g, allura red 0.001g, tartrazine 0.005g, and purified water is diluted to 1000mL.

[0038] The preparation method of acetaminophen oral solution specifically comprises the following steps: adding 500 mL of water to a mixing tank and starting stirring, dissolving sodium citrate, sodium benzoate and sodium saccharin in water according to the above formula and adding them to the mixing tank, then heating and dissolving butylated hydroxyanisole and propylene glycol and adding them to the mixing tank, then adding polyethylene glycol 1500, sorbitol, glycerol and citric acid, heating and boiling, keeping warm and stirring for 30 minutes, then cooling to 55°C, adding acetaminophen, stirring for 20 minutes to dissolve, then cooling to below 40°C, dissolving lemon yellow, allura red and banana essence in water and mixing them, then adding them to the mixing tank, then diluting to 1000 mL with pure water, stirring for 10 minutes, filtering, filling, capping, sealing and packaging to obtain the finished product.

[0039] Among them, the intermediate product obtained after taking pure water to make up the volume is inspected. The appearance of this product should be a rose-red clear liquid with an aromatic odor and a sweet and slightly bitter taste; its relative density should be 1.113-1.233; its pH value should be 4.0-6.0; its para-aminophenol content, calculated by the peak area using the external standard method, should not exceed 0.1% of the labeled amount of acetaminophen; this product should contain 98.0-102.0% of the labeled amount of acetaminophen (C8H9NO2).

[0040] Example 2

[0041] On the basis of Example 1, this example also provides a method for preparing an acetaminophen oral solution, wherein a heat conductive filler (annular, with an average diameter of 3 cm) is contained in a batching tank, and the heat conductive filler can be filtered and recycled before being fixed to volume with pure water. The amount of the heat conductive filler added is 5% of all materials in the batching tank, and the preparation method is as follows:

[0042] (1) Add a mixture of allyl polyoxyethylene ether 350 and an organic peroxide initiator (di-tert-butyl peroxide, the addition amount of which is 2%) to styrene, and react at 70°C for 3 hours to obtain a compatibilizer; the molar ratio of styrene to allyl polyoxyethylene ether is 1:0.8;

[0043] (2) The porous metal fiber and sodium bicarbonate powder were dispersed in a mass ratio of 1:0.05 for 30 minutes, and then mixed with molten polypropylene resin and compatibilizer, and then injection molded at 170°C to obtain the initial filler; the mass ratio of the porous metal fiber, polypropylene resin, and compatibilizer was 0.1:1:0.03;

[0044] (3) Spray 15 times the amount of aluminum chloride solution (mass concentration is 20%) on the surface of the initial filler, let it stand for 30 minutes after spraying, then clean the filler surface with deionized water, and then heat it at 145°C for 30 minutes, and then spray 0.06 times the amount of sealing agent (phenolic resin 50%, anhydrous ethanol 20%, toluene 30%), heat (60°C) and bake for 3 hours, and then wash the filler surface with (8%) acetic acid solution and deionized water in turn, and obtain the thermal conductive filler after drying.

[0045] The rest is the same as Example 1.

[0046] Example 3

[0047] On the basis of Example 2, this example further provides a filter membrane used in a method for preparing an acetaminophen oral solution, wherein the solution is filtered using a filter membrane having a pore size of 0.4 μm after being fixed to volume with pure water. The method for preparing the filter membrane comprises the following steps:

[0048] Mix polyethersulfone, polyamide and N,N-dimethylacetamide evenly, then add polyethylene glycol 400 and additives, stir evenly at 40°C to obtain a transparent casting solution, degas and filter, cast the casting solution on a glass plate at room temperature to form a film, let it stand in the air for 20 minutes, then immerse the glass plate in a coagulation bath (0.2% N,N-dimethylacetamide solution) for 10 seconds to solidify into a film, then soak it in deionized water for 1 day and dry to obtain a filter membrane.

[0049] The mass ratio of polyethersulfone, polyamide, N,N-dimethylacetamide, polyethylene glycol 400 and additives is 1:0.3:1:2:0.12; the additives are additives used in conventional filtration membranes such as polysorbate.

[0050] The rest is the same as Example 2.

[0051] Example 4

[0052] On the basis of Example 3, this example further provides a filter membrane used in a method for preparing an acetaminophen oral solution, and the preparation method of the additive used is:

[0053] S1. Mix 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone evenly, add redox initiator (benzoyl peroxide / N, N-dimethylaniline, 1.5% added) dropwise at 60°C, stir and react for 2h to obtain a copolymer;

[0054] S2. Evenly mix the copolymer and polyethylene glycol 600, then drop the catalyst (boron trifluoride etherate) at 90°C, and stir the mixture for reaction for 36 hours to obtain the additive.

[0055] The molar ratio of polyethylene glycol 600, 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone is 1:1.4:1:1.

[0056] The rest is the same as Example 3.

[0057] Example 5

[0058] On the basis of Example 4, this example further provides a preliminary impurity removal method in the preparation method of acetaminophen oral solution, which includes preliminary impurity removal of the obtained liquid medicine before filtration after the volume is fixed with pure water, and the preliminary impurity removal method is: the obtained liquid medicine is kept at 26° C. for 4 hours, then the keeping temperature is stopped, and 5% impurity remover is added and stirred for 1 hour. The impurity remover is a conventional impurity remover such as activated carbon.

[0059] The rest is the same as Example 4.

[0060] Example 6

[0061] On the basis of Example 5, this embodiment also provides a preliminary impurity removal method in a method for preparing an acetaminophen oral solution, and the preparation method of the impurity remover used comprises the following steps:

[0062] A. Mix heptadecane and dodecanol at a mass ratio of 1:0.5 at 30°C, then add dextrin and water at a mass ratio of 1:1, stir evenly and make 5-mesh granules with a granulator for later use; the total amount of dextrin and water added is 3% of the total amount of heptadecane and dodecanol;

[0063] B. Prepare polyvinyl acetal diethylamine acetate (AEA) into a 5% ethanol solution, then add 0.4 times the amount of molecular sieves and mix evenly, then evenly spray (the spraying amount is 4% of the particles) onto the surface of the particles obtained in step A, and then dry to obtain the impurity remover.

[0064] Example 7

[0065] The present embodiment provides an acetaminophen oral solution, the raw materials for its preparation are: acetaminophen 24g, sorbitol 200g, glycerol 250g, polyethylene glycol 1500 200g, propylene glycol 5g, butylated hydroxyanisole 0.025g, citric acid 6g, sodium citrate 4g, saccharin sodium 5g, sodium benzoate 3g, banana flavor 3g, allure red 0.015g, lemon yellow 0.015g, purified water is set to 1000mL. Its preparation method is the same as that of Example 1.

[0066] The batching tank is filled with a thermal conductive filler (cylindrical, with an average diameter of 5 cm), and the amount of the thermal conductive filler added is 7.5% of all materials. The preparation method is as follows:

[0067] (1) Add a mixture of allyl polyoxyethylene ether 400 and an organic peroxide initiator (diisopropyl peroxydicarbonate, the amount of which is 3%) to styrene, and react at 80°C for 4 hours to obtain a compatibilizer; the molar ratio of styrene to allyl polyoxyethylene ether is 1:1;

[0068] (2) The porous metal fiber and sodium bicarbonate powder were dispersed in a mass ratio of 1:0.08 for 45 minutes, and then mixed with molten polypropylene resin and compatibilizer, and then injection molded at 175°C to obtain the initial filler; the mass ratio of the porous metal fiber, polypropylene resin, and compatibilizer was 0.25:1:0.055;

[0069] (3) Spray 20 times the amount of aluminum chloride solution (mass concentration is 25%) on the surface of the initial filler, let it stand for 35 minutes after spraying, then clean the filler surface with deionized water, and then heat it at 150°C for 40 minutes, and then spray 0.08 times the amount of sealing agent (phenolic resin 60%, anhydrous ethanol 15%, toluene 25%), heat (80°C) and bake for 2 hours, and then wash the filler surface with acetic acid solution (12%) and deionized water in turn. After drying, the thermal conductive filler is obtained.

[0070] The present invention also provides a filter membrane used in a method for preparing an acetaminophen oral solution. After the solution is fixed to volume with pure water, the solution is filtered using a filter membrane with a pore size of 0.45 μm. The method for preparing the filter membrane comprises the following steps:

[0071] Polyethersulfone, polyamide and N,N-dimethylacetamide are mixed evenly, and then polyethylene glycol 600 and additives are added, and stirred evenly at 50°C to obtain a transparent casting solution. After degassing and filtration, the casting solution is cast on a glass plate at room temperature to form a film, and the film is allowed to stand in the air for 30 minutes. The glass plate is then immersed in a coagulation bath (0.2% N,N-dimethylacetamide solution) for 20 seconds to solidify into a film, and then immersed in deionized water for 2 days and dried to obtain the filter membrane.

[0072] The mass ratio of polyethersulfone, polyamide, N,N-dimethylacetamide, polyethylene glycol 600 and additives is 1:0.45:2.5:2.5:0.19.

[0073] The preparation method of the additive is:

[0074] S1. Mix 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone evenly, add a redox initiator (hydrogen peroxide / tartaric acid, the amount of which is 2.2%) dropwise at 70°C, and stir to react for 3.5 hours to obtain a copolymer;

[0075] S2. Evenly mix the copolymer and polyethylene glycol 800, then drop a catalyst (aluminum trichloride ether) at 100° C. and stir to react for 4.5 hours to obtain the additive.

[0076] The molar ratio of polyethylene glycol 800, 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone is 1:1.7:1.25:1.3.

[0077] The present invention also provides a preliminary impurity removal method in the preparation method of acetaminophen oral solution, which includes preliminary impurity removal of the obtained medicinal solution before filtering after the volume is fixed with pure water. The preliminary impurity removal method is: after the obtained medicinal solution is kept warm at 28°C for 7 hours, the keeping warm is stopped, and 7.5% impurity remover is added and stirred for 2 hours.

[0078] The preparation method of the impurity remover comprises the following steps:

[0079] A. Mix heptadecane and dodecanol at a mass ratio of 1:2.2 at 35°C, then add dextrin and water at a mass ratio of 1:2, stir evenly and make 12-mesh granules with a granulator for later use; the total amount of dextrin and water added is 4.5% of the total amount of heptadecane and dodecanol;

[0080] B. Prepare polyvinyl acetal diethylamine acetate (AEA) into a 6% ethanol solution, then add 0.5 times the amount of molecular sieves and mix evenly, then evenly spray (the spraying amount is 7% of the particles) onto the surface of the particles obtained in step A, and then dry to obtain the impurity remover.

[0081] Example 8

[0082] The present embodiment provides an acetaminophen oral solution, the raw materials for its preparation are: 32g acetaminophen, 250g sorbitol, 300g glycerol, 250g polyethylene glycol 1500, 8g propylene glycol, 0.04g butylated hydroxyanisole, 9g citric acid, 6g sodium citrate, 8g saccharin sodium, 5g sodium benzoate, 5g banana flavor, 0.03g allura red, 0.025g lemon yellow, and purified water is set to 1000mL. Its preparation method is the same as that of Example 1.

[0083] The batching tank is filled with a thermal conductive filler (in the form of flakes, with an average diameter of 0.5 cm), and the amount of the thermal conductive filler added is 10% of all the materials. The preparation method is as follows:

[0084] (1) Add a mixture of allyl polyoxyethylene ether 500 and an organic peroxide initiator (benzoyl peroxide, the amount of which is 4%) to styrene, and react at 90°C for 5 hours to obtain a compatibilizer; the molar ratio of styrene to allyl polyoxyethylene ether is 1:1.2;

[0085] (2) The porous metal fiber and sodium bicarbonate powder were dispersed in a mass ratio of 1:0.1 for 60 minutes, and then mixed evenly with molten polypropylene resin and compatibilizer, and then injection molded at 180°C to obtain the initial filler; the mass ratio of the porous metal fiber, polypropylene resin, and compatibilizer was 0.4:1:0.08;

[0086] (3) Spray 25 times the amount of aluminum chloride solution (mass concentration is 30%) on the surface of the initial filler, let it stand for 40 minutes after spraying, then clean the filler surface with deionized water, and then heat it at 155°C for 50 minutes, and then spray 0.1 times the amount of sealing agent (phenolic resin 70%, anhydrous ethanol 10%, toluene 20%), heat (100°C) and bake for 1 hour, and then wash the filler surface with acetic acid solution (15%) and deionized water in turn, and obtain the thermal conductive filler after drying.

[0087] The present invention also provides a filter membrane used in a method for preparing an acetaminophen oral solution. After the solution is fixed to volume with pure water, the solution is filtered using a filter membrane with a pore size of 0.5 μm. The method for preparing the filter membrane comprises the following steps:

[0088] Mix polyethersulfone, polyamide and N,N-dimethylacetamide evenly, then add polyethylene glycol 600 and additives, stir evenly at 60°C to obtain a transparent casting solution, degas and filter, cast the casting solution on a glass plate at room temperature to form a film, let it stand in the air for 40 minutes, then immerse the glass plate in a coagulation bath (0.2% N,N-dimethylacetamide solution) for 30 seconds to solidify it into a film, then soak it in deionized water for 3 days and dry it to obtain a filter membrane.

[0089] The mass ratio of polyethersulfone, polyamide, N,N-dimethylacetamide, polyethylene glycol 600 and additives is 1:0.6:4:3:0.26.

[0090] The preparation method of the additive is:

[0091] S1. Mix 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone evenly, add redox initiator (persulfate / thiol, 3% added) dropwise at 80°C, stir and react for 5 hours to obtain a copolymer;

[0092] S2. The copolymer and polyethylene glycol 800 are uniformly mixed, and then a catalyst (boron trifluoride ethyl ether) is added dropwise at 110° C. and the mixture is stirred for reaction for 6 hours to obtain the additive.

[0093] The molar ratio of polyethylene glycol 800, 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone is 1:2:1.5:1.6.

[0094] The present invention also provides a preliminary impurity removal method in the preparation method of acetaminophen oral solution, which includes preliminary impurity removal of the obtained medicinal solution before filtering after the volume is fixed with pure water. The preliminary impurity removal method is: after the obtained medicinal solution is kept warm at 30°C for 10 hours, the keeping warm is stopped, and 10% impurity remover is added and stirred for 3 hours.

[0095] The preparation method of the impurity remover comprises the following steps:

[0096] A. Mix heptadecane and dodecanol at a mass ratio of 1:4 at 40°C, then add dextrin and water at a mass ratio of 1:3, stir evenly, and make 5-20 mesh granules by a granulator for later use; the total amount of dextrin and water added is 6% of the total amount of heptadecane and dodecanol;

[0097] B. Prepare polyvinyl acetal diethylamine acetate (AEA) into a 7% ethanol solution, then add 0.6 times the amount of molecular sieves and mix evenly, then evenly spray (the spraying amount is 10% of the particles) onto the surface of the particles obtained in step A, and then dry to obtain the impurity remover.

[0098] Comparative Example 1

[0099] The difference between this comparative example and Example 2 is that no compatibilizer is added in the preparation of the thermally conductive filler, and step (1) is not included in this case.

[0100] Comparative Example 2

[0101] The difference between this comparative example and Example 2 is that the compatibilizer in the preparation of the thermally conductive filler is a silane coupling agent.

[0102] Comparative Example 3

[0103] The difference between this comparative example and Example 2 is that the method for preparing the thermally conductive filler does not include step (3).

[0104] Comparative Example 4

[0105] The difference between this comparative example and Example 2 is that step (3) of the preparation method of the thermally conductive filler is: spraying 15 times the amount of aluminum chloride solution on the surface of the initial filler, letting it stand for 30 minutes after spraying, then washing the filler surface with deionized water, then heating it at 145° C. for 30 minutes, then washing the filler surface with acetic acid solution and deionized water in turn, and obtaining the thermally conductive filler after drying.

[0106] 1. Basic parameters of the acetaminophen oral solution prepared by the present invention

[0107] Referring to the relevant standards of the 2020 edition of the "Chinese Pharmacopoeia", the acetaminophen oral solutions prepared in Examples 1-8 of the present invention and Comparative Examples 1-4 were quality tested, and the basic parameter results are shown in Table 1.

[0108] Table 1

[0109]

[0110] It can be seen from Table 1 above that, compared with Example 1, the acetaminophen oral solutions prepared in Examples 2-8 of the present invention have excellent quality, especially in the products of Examples 6, 7, and 8, the actual content of acetaminophen is closest to the labeled amount, which reflects the good dissolution effect of acetaminophen.

[0111] Among them, compared with Example 1, the clarity of the oral solutions of Examples 2-8 of the present invention is better, especially Examples 6, 7, and 8 are all clear solutions. It shows that after using thermal conductive fillers and filter membranes, the oral solutions have less impurities and stable properties.

[0112] Compared with Example 2, Comparative Examples 1-4 respectively changed the preparation method of the thermally conductive filler. As a result, slight precipitation appeared in the oral solution, the actual content of acetaminophen decreased, and the content of acetaminophen also increased slightly, indicating that the thermally conductive filler of the present invention can improve the formulation stability of the oral solution.

[0113] 2. Stability of the acetaminophen oral solution prepared by the present invention

[0114] The acetaminophen oral solutions prepared in Examples 1-8 of the present invention and Comparative Examples 1-4 were placed at room temperature for 2 years, and samples were kept for observation at 0, 6, 12, 18, and 24 months. As a result, there was no significant change in the product appearance, pH value, and acetaminophen content of Examples 6, 7, and 8. The product appearance, pH value, and acetaminophen content of Examples 1-5 and Comparative Examples 1-4 are shown in Table 2.

[0115] Table 2

[0116]

[0117] The products of Examples 6, 7 and 8 of the present invention showed no significant changes after being placed for 24 months, indicating that they have good stability in all aspects. The stability of their clarity also further demonstrates that their impurity content is low and the dissolution effect of acetaminophen is good.

[0118] From the results in Table 2, it can be seen that the clarity, pH value and acetaminophen of the products of Examples 1-8 and Comparative Examples 1-4 began to change successively in different months, and the degree of change is compared: Example 1> Comparative Example 1> Comparative Example 2=Comparative Example 4> Comparative Example 3> Example 2> Example 4> Example 3> Example 5. The greater the degree of change, the worse the stability.

[0119] Compared with Example 1, Example 2 uses a thermally conductive filler, and the stability of the oral liquid is significantly improved. On the basis of Example 2, Examples 3 and 4 use a filter membrane to improve the filtration efficiency and reduce the impurity content. As a result, the stability of the oral liquid is slightly improved, but at the same time, the dissolved portion of the insoluble impurities also increases, so there is still some instability. On the basis of Example 4, Examples 5, 6, 7, and 8 further use a preliminary impurity removal method to remove the dissolved portion of the insoluble impurities in the product, ultimately ensuring the stability of the product.

[0120] 3. Thermal conductivity of the thermally conductive filler prepared by the present invention

[0121] According to Fourier's law, the thermal conductivity of the thermally conductive fillers prepared in Examples 2, 7, 8 of the present invention and Comparative Examples 1-4 was measured using a heat flow meter method. The results are shown in Table 3.

[0122] Table 3

[0123]

[0124] From the results in Table 3, it can be seen that the thermal conductivity of the thermally conductive filler prepared by the present invention is 5.3-5.6 W / m·k. Compared with Example 2, the thermal conductivity of the thermally conductive fillers in Comparative Examples 1-4 is significantly reduced, indicating that the preparation method of the thermally conductive filler of the present invention can improve the thermal conductivity of the filler.

[0125] 4. Performance parameters of the filter membrane prepared by the present invention

[0126] The performance of the filtration membranes prepared in Examples 3, 6-8 of the present invention was measured, and the results of pure water flux and retention rate are shown in Table 4.

[0127] Pure water flux = permeable water volume in time t / (membrane area × t). The measurement pressure is 0.1 MPa.

[0128] Retention rate = (1-concentration of a certain solute in the permeate / concentration of a certain solute in the raw material solution) × 100%. In this test, 0.05% BSA (bovine serum albumin) was used to determine the BSA retention rate.

[0129] Porosity = volume of membrane pores / apparent volume of membrane, measured by weighing method.

[0130] Table 4

[0131]

[0132] From the results in Table 4, it can be seen that the pure water flux of the filtration membrane prepared by the present invention is 800 L﹒ m -2 ﹒h -1The interception rate is above 93%, and the porosity is above 77%. The performance of the filtration membranes in Examples 6, 7, and 8 is better, and the pure water flux is up to 976.4 L﹒ m -2 ﹒h -1 The highest interception rate reached 97.8%, and the highest porosity reached 84.8%.

[0133] The beneficial effects of the present invention are as follows: the present invention provides a method for preparing an acetaminophen oral solution, which comprehensively improves the product quality through the design of a thermal conductive filler, a filter membrane and a preliminary impurity removal method.

[0134] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an acetaminophen oral solution, characterized in that: The specific steps include: Add 500 mL of water to the batching tank and start stirring. Dissolve sodium citrate, sodium benzoate and sodium saccharin in water and add them to the batching tank. Then heat and dissolve butylated hydroxyanisole and propylene glycol and add them to the batching tank. Then add polyethylene glycol 1500, sorbitol, glycerin and citric acid. Heat and boil, keep warm and stir for 30 minutes, then cool to 55°C, add acetaminophen, stir for 20 minutes to dissolve, then cool to below 40°C, dissolve lemon yellow, allura red and banana flavor in water, mix well and add them to the batching tank, then dilute to 1000 mL with pure water, stir for 10 minutes, filter, fill, cap, seal and package to obtain the finished product. The batching tank is filled with a thermal conductive filler, and the amount of the thermal conductive filler added is 5-10% of all materials. The preparation method is as follows: (1) Add a mixed solution of allyl polyoxyethylene ether and an organic peroxide initiator dropwise into styrene and react at 70-90°C for 3-5 hours to obtain a compatibilizer; (2) The porous metal fiber and the sodium bicarbonate powder are dispersed for 30 to 60 minutes, and then mixed with the molten polypropylene resin and the compatibilizer, and then injection molded at 170 to 180° C. to obtain the initial filler; (3) Spray the surface of the initial filler with aluminum chloride solution, heat it at 145-155°C for 30-50 minutes, spray a sealing agent, heat and bake, and obtain a thermally conductive filler; After the volume is fixed with pure water, the filter is filtered using a filter membrane with a pore size of 0.4 to 0.5 μm. The preparation method of the filter membrane comprises the following steps: The polyethersulfone, polyamide and N,N-dimethylacetamide are mixed evenly, and then polyethylene glycol 400 or 600 and additives are added, and stirred evenly at 40-60° C. to obtain a transparent casting solution, and after degassing and filtering, the casting solution is cast on a glass plate at room temperature to form a film, and the film is allowed to stand in the air for 20-40 minutes, and then the glass plate is immersed in a coagulation bath for 10-30 seconds to solidify into a film, and then immersed in deionized water for 1-3 days, and dried to obtain the filter membrane; The preparation method of the additive is: S1. Mix 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone evenly, add a redox initiator dropwise at 60-80° C. and stir for 2-5 hours to obtain a copolymer; S2, mixing the copolymer and polyethylene glycol 600 or 800 evenly, then adding the catalyst dropwise at 90-110° C., stirring and reacting for 3-6 hours, to obtain the additive; After the pure water is fixed to volume, before filtering, the obtained liquid medicine is subjected to preliminary impurity removal. The preliminary impurity removal method is as follows: the obtained liquid medicine is kept at 26-30°C for 4-10 hours, then the keeping temperature is stopped, 5-10% impurity remover is added, and stirred for 1-3 hours. The preparation method of the impurity remover comprises the following steps: A. Mix heptadecane and dodecanol at 30-40°C, then add dextrin and water, stir evenly and make into 5-20 mesh granules by granulator for later use; B. Prepare 5-7% ethanol solution of polyvinyl acetal diethylamine acetate, then add molecular sieve and mix evenly, then spray evenly on the surface of the particles obtained in step A, and then dry to obtain the impurity remover.

2. The method for preparing the acetaminophen oral solution according to claim 1, wherein: The acetaminophen oral solution is prepared from the following raw materials: 24-32g of acetaminophen, 150-250g of sorbitol, 200-300g of glycerol, 150-250g of polyethylene glycol 1500, 2-8g of propylene glycol, 0.01-0.04g of butylated hydroxyanisole, 3-9g of citric acid, 2-6g of sodium citrate, 2-8g of sodium saccharin, 1-5g of sodium benzoate, 1-5g of banana flavor, 0.001-0.03g of allura red, 0.005-0.025g of tartrazine, and the volume is made up to 1000mL with purified water.

3. The method for preparing the acetaminophen oral solution according to claim 1, wherein: In step (1), the molar ratio of styrene to allyl polyoxyethylene ether is 1:(0.8-1.2), and the amount of organic peroxide initiator added is 2-4%; in step (2), the mass ratio of porous metal fiber, polypropylene resin and compatibilizer is (0.1-0.4):1:(0.03-0.08), and the mass ratio of porous metal fiber to sodium bicarbonate powder is 1:(0.05-0.1); in step (3), the mass concentration of aluminum chloride solution is 20-30%, and the injection amount thereof is 15-25 times the mass of sodium bicarbonate powder. The mass ratio of sealing agent to initial filler is (0.06-0.1):1, and the sealing agent is air-dried phenolic resin.

4. The method for preparing the acetaminophen oral solution according to claim 1, wherein: The mass ratio of the polyethersulfone, polyamide, N,N-dimethylacetamide, polyethylene glycol 400 or 600, and additives is 1: (0.3-0.6): (1-4): (2-3): (0.12-0.26).

5. The method for preparing the acetaminophen oral solution according to claim 1, wherein: The molar ratio of polyethylene glycol 600 or 800, 3,4-epoxy-1-butene, styrene and N-vinyl pyrrolidone is 1:(1.4-2):(1-1.5):(1-1.6); in step S1, the amount of the redox initiator added is 1.5-3%; in step S2, the catalyst is boron trifluoride etherate or aluminum trichloride etherate.

6. The method for preparing the acetaminophen oral solution according to claim 1, wherein: In step A, the mass ratio of heptadecane to dodecanol is 1:(0.5-4), the mass ratio of dextrin to water is 1:(1-3), and the total amount of dextrin and water added is 3-6% of the total amount of heptadecane and dodecanol; in step B, the mass ratio of solution to molecular sieve is 1:(0.4-0.6), and the injection amount is 4-10% of the particles.

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