A method of recovering acetaminophen

Abstract

The application discloses a method for recovering paracetamol, which comprises the following steps: dissolving substandard paracetamol particles in water, cooling, and removing most of starch-containing accessories in the particles; since the crystal particles of paracetamol product in the system are large and easy to precipitate, the paracetamol product can be obtained by fully utilizing the cooling and standing; the paste solution formed in the heating process of the starch accessories can be effectively separated by means of simple decantation; the first clear liquid can be continuously separated by decantation after standing to obtain the second solid paracetamol; and the solid particles of the two times are combined and refined. The recovery method is simple and easy to operate as a whole, does not need to use ethanol as a solvent, is low in cost, high in recovery rate, and can provide a reference for industrial-scale recovery of substandard paracetamol particles.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical recycling technology, specifically a method for recycling acetaminophen. Background Technology

[0002] The structural formula of acetaminophen (N-(4-hydroxyphenyl)acetamide, CAS No.: 103-90-2) is:

[0003]

[0004] Acetaminophen is an antipyretic, analgesic, and nonsteroidal anti-inflammatory drug. Its antipyretic effect is slow and long-lasting, and compared to aspirin, it has advantages such as less irritation and very few allergic reactions. Acetaminophen can also be used as a pharmaceutical intermediate for benorilates, sulfathiazoles, omeprazoles, and purine derivatives. Besides its pharmaceutical uses, it also has industrial applications such as an auxiliary agent in the dye industry, an additive in the chemical industry, a contrast agent for medical X-ray films, and an anti-aging agent for rubber products.

[0005] Acetaminophen contains an amide bond and a phenolic hydroxyl group in its structural formula, which makes it highly reactive and easily oxidized. Under humid conditions, it easily molds and clumps, its appearance changing from white to pink or even brown. Acetaminophen formulation granules include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, and hydroxypropyl cellulose, among other ingredients. The acetaminophen content in the granules is 90%, while the content of starch excipients such as starch, pregelatinized starch, and sodium carboxymethyl starch is approximately 8.5%. Due to improper storage, acetaminophen granules and tablets may mold, clump, and turn pink, resulting in substandard quality. Simply discarding and destroying substandard acetaminophen granules not only causes property damage but also increases the risk of environmental pollution.

[0006] The literature "Extraction and Production Implementation of Acetaminophen from Unqualified Compressed Granules" (Chemical Industry Progress, 2012, 31(2): 473-475) reports the processing technology for unqualified acetaminophen tablet granules: 95% ethanol is used as a solvent to dissolve the granules, and excipients such as starch are removed by filtration. After the filtrate is recovered, the remaining concentrate is decolorized with water, and after filtration, the filtrate is cooled to crystallize. After filtration and drying, acetaminophen is obtained. In order to ensure the recovery rate, the mother liquor wastewater after crystallization and filtration needs to be concentrated, cooled to crystallize, and centrifuged again to obtain crude product, which is then combined with the crude product obtained from concentrated ethanol for further treatment. The average recovery rate of acetaminophen reaches 89.4%.

[0007] The aforementioned acetaminophen recovery process has the following drawbacks: The process uses 95% ethanol as a solvent. Since acetaminophen's market price is around 25,000 yuan / ton and industrial ethanol's market price is around 8,000 yuan / ton, the industrial ethanol recovery process is costly. More importantly, after the granules are dissolved in 95% ethanol, filtration becomes very difficult. Even with filter aids such as diatomaceous earth to extend the filtration time, it is difficult to completely filter the granule solution. In industrial-scale production, this filtration problem cannot be solved by centrifugal filtration, filter press filtration, or reduced-pressure filtration. This not only affects the production cycle but also directly impacts the process yield due to the inability to completely separate the granule solution from the filter cake. It should be noted that if the granules are dissolved in water before filtration, the same filtration difficulties will arise. The root cause of these difficulties is that the granule formulation typically contains pregelatinized starch, sodium carboxymethyl starch, and other starch-containing ingredients. These starch-containing excipients form a paste-like solution during heating, clogging the pores of the filter medium and leading to filtration difficulties.

[0008] Existing technologies for recovering acetaminophen from substandard acetaminophen tablets suffer from high recovery costs; long filtration cycles after dissolving the particles in 95% ethanol; and incomplete solid-liquid separation during the filtration process, all of which affect the recovery rate. Summary of the Invention

[0009] The acetaminophen formulation granules include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, hydroxypropyl cellulose, and other ingredients. The acetaminophen granules in this invention contain 90% acetaminophen, and the content of starch-based excipients such as starch, pregelatinized starch, and sodium carboxymethyl starch is approximately 8.5%. A small amount of material discoloration is observed in the granules. The purpose of this invention is to provide a method for recovering acetaminophen, addressing the shortcomings of existing technologies such as high recovery costs, long cycles, difficulties in industrial implementation, and low recovery rates.

[0010] In view of this, the solution of the present invention is as follows:

[0011] A method for recovering acetaminophen, comprising the steps of:

[0012] S1. Add the substandard acetaminophen granules and the first reducing agent to water, heat to 95-100℃ with stirring and dissolve for 0.5-1h, cool and let stand, and decant to separate to obtain the first clear liquid and the first solid; the mass ratio of substandard acetaminophen granules to water is (3.5-5):1;

[0013] S2. Let the first clear liquid stand until it stabilizes, then decant to obtain the second solid;

[0014] S3. Add the second reducing agent and water to the first and second solids, heat to 95-100℃ with stirring to fully dissolve, add carbon to decolorize, filter, cool the filtrate to precipitate crystals, filter, and dry to obtain acetaminophen; the mass ratio of the total amount of solids to water during the dissolution process is (3-4):1.

[0015] Furthermore, the substandard acetaminophen granules include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, and hydroxypropyl cellulose, with an acetaminophen content of less than 90%.

[0016] Furthermore, the first reducing agent and / or the second reducing agent are each independently selected from at least one of sodium bisulfite and sodium metabisulfite.

[0017] Furthermore, in step S1, the cooling and settling conditions are 1-5°C and settling for 1-2 hours.

[0018] Furthermore, in step S2, the settling conditions are 5-10°C and 12-24 hours.

[0019] Furthermore, in step S3, the dissolution process lasts for 0.5 hours.

[0020] Furthermore, in step S3, the filtrate is cooled and crystallized under the following conditions: 0–5°C for 2–5 hours.

[0021] Another objective of this invention is to provide acetaminophen obtained by the above-described recovery method with a purity greater than 99.98%.

[0022] Another object of the present invention is to provide uses for the recovered acetaminophen, said uses including at least one of the following non-pharmaceutical and pharmaceutical synthesis:

[0023] a) Dye industry auxiliaries;

[0024] b) Pesticide synthesis intermediates;

[0025] c) Contrast agents for medical X-ray films;

[0026] d) Anti-aging agents for rubber products.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] The recovery method of this invention involves dissolving substandard acetaminophen granules in water and then cooling the solution to separate and remove most of the starch-containing excipients from the granules. Since the acetaminophen crystals in the system are large and easily precipitate, cooling and settling are fully utilized to obtain the final product. The starch-containing excipients, which form a paste-like solution during heating and float on the surface, can be effectively separated using a simple decantation method. After settling, the first supernatant can be further separated by decantation to obtain a second solid acetaminophen. The two lower solid particles are then combined and purified. The recovery method is simple and easy to implement, requires no ethanol as a solvent, is low-cost, and has a high recovery rate, providing a reference for the industrial-scale recovery of substandard acetaminophen granules. Detailed Implementation

[0029] The technical solution of the present invention will be clearly and completely described and verified below with reference to preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0030] For reagents or instruments whose manufacturers are not specified in the examples, these can be purchased from the market as standard products. For items whose specific conditions are not specified, standard conditions or manufacturer-recommended conditions should be followed.

[0031] In the embodiments of this invention, the acetaminophen granules contain 90% acetaminophen. In the following embodiments, the acetaminophen content in the substandard acetaminophen granules was found to be 86.1%.

[0032] Example 1

[0033] Add 5g of sodium bisulfite, 100g of substandard acetaminophen granules, and 350g of primary water to a reaction flask. Heat to 95℃, then maintain the temperature at 95℃~100℃ with stirring for 0.5 hours. Cool to 5℃ and let stand at 1℃~5℃ for 2 hours. Separate the primary upper layer solution by decantation to obtain the primary lower layer precipitate. Let the primary upper layer solution stand at 5℃~10℃ for 24 hours, then separate and remove the secondary upper layer solution by decantation to obtain the secondary lower layer precipitate. 5g of sodium bisulfite and 400g of deionized water were added to the lower layers of the first and second layers. The mixture was heated to 95℃ and then kept at 95℃-100℃ with stirring for 0.5 hours. 8g of activated carbon was added, and the mixture was kept at 95℃-100℃ with stirring for another 0.5 hours. The mixture was filtered, and the filtrate was cooled to 5℃ and stirred at 0℃-5℃ to crystallize for 2 hours. After filtration and drying, 79.5g of acetaminophen was obtained with an HPLC purity of 99.99% and a yield of 92.33%.

[0034] Example 2

[0035] 2g of sodium metabisulfite, 100g of substandard acetaminophen granules, and 500g of primary water were added to a reaction flask. The mixture was heated to 95℃, then kept at 95℃~100℃ with stirring for 1 hour. The temperature was then lowered to 5℃, and the mixture was allowed to stand at 1℃~5℃ for 1 hour. The primary upper layer was separated by decantation to obtain the primary lower layer precipitate. The primary upper layer was then allowed to stand at 5℃~10℃ for 12 hours, and the secondary upper layer was removed by decantation to obtain the secondary lower layer precipitate. 2g of sodium metabisulfite and 300g of deionized water were added to the lower layers of the first and second stages. The mixture was heated to 95°C and then kept at 95°C–100°C with stirring for 0.5 hours. 8g of activated carbon was added, and the mixture was kept at 95°C–100°C with stirring for another 0.5 hours. The mixture was filtered, and the filtrate was cooled to 5°C. Crystallization was carried out at 0°C–5°C with stirring for 5 hours. After filtration and drying, 79.7g of acetaminophen was obtained with an HPLC purity of 99.98% and a yield of 92.57%.

[0036] Example 3

[0037] 2g of sodium metabisulfite, 100g of substandard acetaminophen granules, and 400g of primary water were added to a reaction flask. The mixture was heated to 95℃, then kept at 95℃~100℃ with stirring for 0.5 hours. The temperature was then lowered to 5℃, and the mixture was allowed to stand at 1℃~5℃ for 2 hours. The primary upper layer was separated by decantation to obtain the primary lower layer precipitate. The primary upper layer was then allowed to stand at 5℃~10℃ for 16 hours, and the secondary upper layer was removed by decantation to obtain the secondary lower layer precipitate. 2g of sodium metabisulfite and 350g of deionized water were added to the lower layers of the first and second stages. The mixture was heated to 95℃ and then kept at 95℃-100℃ with stirring for 0.5 hours. 8g of activated carbon was added, and the mixture was kept at 95℃-100℃ with stirring for another 0.5 hours. The mixture was filtered, and the filtrate was cooled to 5℃ and stirred at 0℃-5℃ to crystallize for 3 hours. After filtration and drying, 79.3g of acetaminophen was obtained with an HPLC purity of 99.99% and a yield of 92.10%.

[0038] Comparative Example 1

[0039] 5g of sodium bisulfite, 100g of substandard acetaminophen granules, and 350g of primary water were added to a reaction flask. The temperature was raised to 95℃, and then kept at 95℃~100℃ with stirring for 0.5 hours. The temperature was then lowered to 5℃ and allowed to stand at 1℃~5℃ for 2 hours. Conventional filtration (atmospheric pressure and vacuum) was used, but it was found that the paste-like substance severely clogged the filter medium, making the process impossible.

[0040] Comparative Example 2

[0041] 5g of sodium bisulfite, 100g of substandard acetaminophen granules, and 350g of primary water were added to a reaction flask. The mixture was heated to 95℃ and then stirred at 95℃-100℃ for 0.5 hours. The temperature was then lowered to 5℃ and allowed to stand at 1℃-5℃ for 2 hours. The lower precipitate was obtained by decantation. 5g of sodium bisulfite, 400g of secondary water, and the lower precipitate were added to a reaction flask. The mixture was heated to 95℃ and stirred at 95℃-100℃ for 0.5 hours. 8g of activated carbon was added, and the mixture was stirred at 95℃-100℃ for another 0.5 hours. The mixture was filtered, and the filtrate was cooled to 5℃ and stirred at 0℃-5℃ for 2 hours to crystallize. After filtration and drying, 71.2g of acetaminophen was obtained with an HPLC purity of 99.99% and a yield of 82.69%.

[0042] Comparative Example 3

[0043] The method for treating substandard acetaminophen particles is the same as in Example 1, except that sodium bisulfite is not added. The final acetaminophen obtained has an HPLC purity of 99.59%. Among the related substances, the impurity content of acetaminophen is 0.005%, which poses a risk of exceeding the limit.

[0044] As can be seen from Examples 1-3 above, under the protection of a reducing agent, the substandard particles are first dissolved by heating, then cooled and decanted to separate the upper liquid and lower solid. After the upper liquid is allowed to stand and the lower solid precipitates, it is combined with the previous lower solid and heated again. Activated carbon is added for decolorization. After filtration and cooling crystallization, a high-purity acetaminophen recovery product can be obtained, with a recovery rate of over 92%. Due to the influence of heating to dissolve the particles, pregelatinized starch, sodium carboxymethyl starch, and starch gelatinize, which restricts the use of ordinary filtration methods. Therefore, the ordinary filtration method in Comparative Example 1 cannot be successfully carried out. It is evident from Comparative Example 2 that a certain amount of acetaminophen still exists in the upper liquid after the first heating, thus leading to a decrease in the recovery rate. In Comparative Example 3, without the addition of a reducing agent, the purity of the acetaminophen product in the liquid phase is reduced, and the content of acetaminophen is too high, posing a risk of exceeding the limit. As can be seen from the above examples, the water-based dissolution method can completely achieve the recovery of acetaminophen, avoiding the cost increase caused by the use of organic solvents such as ethanol, and has significant prospects for industrial application.

[0045] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for recovering acetaminophen, characterized in that the steps include... include: S1. Add the substandard acetaminophen granules and the first reducing agent to water, heat to 95-100℃ with stirring and dissolve for 0.5-1h, cool and let stand, and decant to separate to obtain the first clear liquid and the first solid; the mass ratio of substandard acetaminophen granules to water is (3.5-5):1; S2. Let the first clear liquid stand until it stabilizes, then decant to obtain the second solid; S3. Add the second reducing agent and water to the first and second solids, heat to 95-100℃ with stirring to fully dissolve, add carbon to decolorize, filter, cool the filtrate to crystallize, filter, and dry to obtain acetaminophen; the mass ratio of the total amount of solid to water during the dissolution process is (3-4):

1. The substandard acetaminophen granules include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, and hydroxypropyl cellulose, with an acetaminophen content of less than 90%. The first reducing agent and the second reducing agent are each independently selected from at least one of sodium bisulfite and sodium metabisulfite.

2. The method according to claim 1, characterized in that, In step S1, the cooling and settling conditions are 1-5°C and settling for 1-2 hours.

3. The method according to claim 1, characterized in that, In step S2, the settling conditions are 5-10°C and 12-24 hours.

4. The method according to claim 1, characterized in that, In step S3, the dissolution process lasts for 0.5 hours.

5. The method according to claim 1, characterized in that, In step S3, the filtrate is cooled and crystallized under the following conditions: 0–5°C for 2–5 hours.

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