Method for recovering acetaminophen

Abstract

The invention discloses a method for recovering acetaminophen, which comprises the following steps: adding water into unqualified acetaminophen particles, dissolving, cooling, separating to remove most starch-containing auxiliary materials in the particles, and sufficiently cooling and standing because the acetaminophen product in the system has large crystal particles and is easy to precipitate; due to the characteristic that a pasty solution formed in the heating process of the starch auxiliary materials floats on the upper layer of the system, effective separation can be carried out by virtue of a simple decantation method; standing the first clear liquid, continuously separating by using the decantation method to obtain a second solid acetaminophen, and combining and refining lower-layer solid particles obtained by two times to obtain the acetaminophen. The recovery method is simple and feasible on the whole, does not need to use ethanol as a solvent, is low in cost and high in recovery rate, and can provide reference for industrial large-scale recovery of unqualified acetaminophen particles.

Description

Technical Field

[0001] The invention relates to the technical field of drug recovery, in particular to a method for recovering acetaminophen. Background Art

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

[0003]

[0004] Acetaminophen is an antipyretic, analgesic, and non-steroidal anti-inflammatory drug. Its antipyretic effect is slow and lasting. Compared with aspirin, it has the advantages of less irritation and rarely causes allergic reactions. Acetaminophen can also be used as a pharmaceutical intermediate for benolate, sulfathiazole, omeprazole, and purine derivatives. In addition to pharmaceutical uses, it can also be used as an auxiliary agent in the dye industry, an additive in the chemical industry, a developer for medical X-ray films, and an anti-aging agent for rubber products.

[0005] The structural formula of acetaminophen contains amide bonds and phenolic hydroxyl groups. Its structural characteristics determine that the compound is active and easily oxidized. It is easy to mold and clump under humid conditions, and the appearance color gradually changes from white to pink or even brown. The acetaminophen prescription granules include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, hydroxypropyl cellulose and other ingredients. The acetaminophen content in the acetaminophen granules is 90% of the specification, and the content of starch excipients such as starch, pregelatinized starch, sodium carboxymethyl starch is about 8.5%. Due to improper storage and other reasons, acetaminophen granules and acetaminophen compressed granules may become moldy and clump, and the appearance will turn pink, resulting in unqualified quality. If the unqualified acetaminophen granules are simply scrapped and destroyed, it will not only cause property losses, but also increase the risk of environmental pollution.

[0006] The document "Extraction and Production Implementation of Paracetamol in Substandard Tablet Granules" (Chemical Industry Progress, 2012, 31 (2): 473-475) reported the processing technology of substandard paracetamol tablet granules: using 95% ethanol as a solvent to dissolve the granules, filtering to remove auxiliary materials such as starch, adding water to the remaining concentrate after the filtrate is recovered for decolorization, cooling the filtrate after filtration for crystallization, and then filtering and drying to obtain the paracetamol product. In order to ensure the recovery rate, the mother liquor wastewater after crystallization filtration needs to be concentrated again, cooled and crystallized, centrifuged, etc. to obtain the crude product obtained by the steps of concentrating the ethanol and the crude product is combined for treatment, and the average recovery rate of paracetamol reaches 89.4%.

[0007] The above-mentioned acetaminophen recovery process has the following defects: the recovery process uses 95% ethanol as a solvent. Since the market price of acetaminophen is about 25,000 yuan / ton and the market price of industrial ethanol is about 8,000 yuan / ton, the cost of the industrial ethanol recovery process is relatively high; more importantly, after the particles are dissolved in 95% ethanol, the filtering operation is difficult to implement. Even if filter aids such as diatomaceous earth are used to extend the filtration time, it is difficult to filter the particle dissolution solution clean. In the industrialized production stage, whether the filtration is performed by centrifuge or filter press, vacuum filtration, etc., the filtration step cannot solve the problem of filtration difficulties, which will not only affect the production cycle, but also fail to completely separate the particle solution and the filter cake, which will directly affect the yield level of the process. It should be pointed out that if the particles are dissolved in water and then filtered, they will also face the situation of filtration difficulties. The fundamental reason for the difficulty in filtration is that the granule prescription usually contains pregelatinized starch, sodium carboxymethyl starch, starch and other ingredients. These starch-containing auxiliary materials will form a pasty solution during the heating process, blocking the gaps in the filter medium and causing difficulty in filtration.

[0008] The existing technology for recovering acetaminophen from unqualified acetaminophen tablet granules has the problems of high recovery cost, long filtration cycle after dissolving the granules in 95% ethanol, and incomplete solid-liquid separation in the filtration process affecting the recovery rate. Summary of the invention

[0009] The acetaminophen prescription granule product includes starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, hydroxypropyl cellulose and other ingredients. The acetaminophen content in the acetaminophen granules of the present invention is 90% of the specification, and the content of starch excipients such as starch, pregelatinized starch, sodium carboxymethyl starch is about 8.5%, and a small amount of material discoloration occurs in the granules. The present invention aims to provide a method for recovering acetaminophen, which is used to solve the defects of high recovery cost, long cycle, difficulty in industrial implementation and low recovery rate in the prior art.

[0010] In view of this, the scheme of the present invention is:

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

[0012] S1. Add unqualified acetaminophen particles and a first reducing agent to water, heat to 95-100° C. under stirring to dissolve for 0.5-1h, cool to stand, and decant to separate to obtain a first clear liquid and a first solid; the mass ratio of unqualified acetaminophen particles to water is (3.5-5):1;

[0013] S2. The first clear liquid is allowed to stand until it is stable, and the second solid is obtained by decantation separation;

[0014] S3. Add the second reducing agent and water to the first solid and the second solid, heat to 95-100°C with stirring to fully dissolve, add charcoal for decolorization, filter, cool the filtrate for crystallization, filter, and dry to obtain acetaminophen; the mass ratio of the total solid to water during the dissolution process is (3-4):1.

[0015] Furthermore, the unqualified acetaminophen particles include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, and hydroxypropyl cellulose, and the acetaminophen content is 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 pyrosulfite.

[0017] Furthermore, in step S1, the cooling and standing condition is 1-5°C for 1-2h.

[0018] Furthermore, in step S2, the standing condition is 5-10° C. and the standing time is 12-24 hours.

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

[0020] Furthermore, in step S3, the filtrate is cooled and crystallized at 0 to 5°C for 2 to 5 hours.

[0021] Another object of the present invention is to provide the acetaminophen obtained by the above recovery method, the purity of which is greater than 99.98%.

[0022] Another object of the present invention is to provide the use of the recovered acetaminophen, which includes at least one of the following non-pharmaceutical and pharmaceutical synthesis:

[0023] a) Auxiliary agents for dye industry;

[0024] b) Pesticide synthesis intermediates;

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

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

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The recovery method of the present invention dissolves unqualified acetaminophen particles in water and then cools them down to separate and remove most of the starch-containing auxiliary materials in the particles. Since the crystalline particles of the acetaminophen product in the system are large and easy to precipitate, the acetaminophen product can be obtained by fully utilizing the cooling and standing. The pasty solution formed during the heating process of the starch auxiliary material floats on the upper layer of the system and can be effectively separated by a simple decantation method. After standing, the first clear liquid can continue to be separated by decantation to obtain the second solid acetaminophen, and the two lower solid particles are combined and refined. The recovery method is simple and easy as a whole, does not need to use ethanol as a solvent, has low cost, and has a high recovery rate. It can provide a reference for industrial-scale recovery of unqualified acetaminophen particles. DETAILED DESCRIPTION

[0029] The technical solution of the present invention will be clearly and completely described and verified in conjunction with the preferred embodiments of the present invention. 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.

[0030] If the manufacturer of reagents or instruments is not specified in the examples, conventional products can be purchased from the market. If specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer can be used.

[0031] The content of acetaminophen in the acetaminophen granules in the embodiment of the present invention is 90% of the specification, and the content of acetaminophen in the unqualified acetaminophen granules in the following embodiment is 86.1% after detection.

[0032] Example 1

[0033] 5g of sodium bisulfite, 100g of unqualified acetaminophen granules and 350g of primary water were put into a reaction bottle, heated to 95°C, then kept and stirred at 95°C to 100°C for 0.5 hours, cooled to 5°C, and allowed to stand at 1°C to 5°C for 2 hours, and the primary upper layer solution was separated by decantation to obtain the primary lower layer precipitated particles. The primary upper layer solution was continued to stand at 5°C to 10°C for 24 hours, and the secondary upper layer solution was separated by decantation to obtain the secondary lower layer precipitated particles. Add 5 g of sodium bisulfite and 400 g of secondary water to the primary lower layer and the secondary lower layer, raise the temperature to 95°C, then keep stirring at 95°C-100°C for 0.5 hour, add 8 g of activated carbon, continue to keep stirring at 95°C-100°C for 0.5 hour, filter, cool the filtrate to 5°C, stir and crystallize at 0°C-5°C for 2 hours, filter and dry to obtain 79.5 g of acetaminophen with HPLC purity of 99.99% and yield of 92.33%.

[0034] Example 2

[0035] 2g of sodium pyrosulfite, 100g of unqualified acetaminophen granules and 500g of primary water were put into a reaction bottle, heated to 95°C, then kept and stirred at 95°C to 100°C for 1 hour, cooled to 5°C, and allowed to stand at 1°C to 5°C for 1 hour, and the primary upper layer solution was separated by decantation to obtain the primary lower layer precipitated particles. The primary upper layer solution was continued to stand at 5°C to 10°C for 12 hours, and the secondary upper layer solution was separated by decantation to obtain the secondary lower layer precipitated particles. Add 2 g of sodium metabisulfite and 300 g of secondary water to the primary lower layer and the secondary lower layer, raise the temperature to 95°C, then keep stirring at 95°C-100°C for 0.5 hour, add 8 g of activated carbon, continue to keep stirring at 95°C-100°C for 0.5 hour, filter, cool the filtrate to 5°C, stir and crystallize at 0°C-5°C for 5 hours, filter and dry to obtain 79.7 g of acetaminophen with HPLC purity of 99.98% and yield of 92.57%.

[0036] Example 3

[0037] 2g of sodium pyrosulfite, 100g of unqualified acetaminophen granules and 400g of primary water were put into a reaction bottle, heated to 95°C, then kept and stirred at 95°C to 100°C for 0.5 hours, cooled to 5°C, and allowed to stand at 1°C to 5°C for 2 hours, and the primary upper layer solution was separated by decantation to obtain the primary lower layer precipitated particles. The primary upper layer solution was continued to stand at 5°C to 10°C for 16 hours, and the secondary upper layer solution was separated by decantation to obtain the secondary lower layer precipitated particles. Add 2 g of sodium metabisulfite and 350 g of secondary water to the primary lower layer and the secondary lower layer, raise the temperature to 95°C, then keep stirring at 95°C-100°C for 0.5 hour, add 8 g of activated carbon, continue to keep stirring at 95°C-100°C for 0.5 hour, filter, cool the filtrate to 5°C, stir and crystallize at 0°C-5°C for 3 hours, filter and dry to obtain 79.3 g of acetaminophen with HPLC purity of 99.99% and yield of 92.10%.

[0038] Comparative Example 1

[0039] 5 g of sodium bisulfite, 100 g of unqualified acetaminophen granules and 350 g of primary water were put into a reaction bottle, the temperature was raised to 95°C, then kept stirring at 95°C-100°C for 0.5 hour, cooled to 5°C, and allowed to stand at 1°C-5°C for 2 hours. Conventional filtration (normal pressure and vacuum) was used, and it was found that the paste severely blocked the filter medium and could not be carried out.

[0040] Comparative Example 2

[0041] 5g of sodium bisulfite, 100g of unqualified paracetamol particles, and 350g of primary water were put into a reaction bottle, heated to 95°C, then stirred at 95°C to 100°C for 0.5 hours, cooled to 5°C, and allowed to stand at 1°C to 5°C for 2 hours, and the lower layer precipitated particles were separated by decantation. 5g of sodium bisulfite, 400g of secondary water, and the lower layer were put into a reaction bottle, heated to 95°C, then stirred at 95°C to 100°C for 0.5 hours, 8g of activated carbon were added, and stirred at 95°C to 100°C for 0.5 hours, filtered, the filtrate was cooled to 5°C, stirred and crystallized at 0°C to 5°C for 2 hours, filtered, and dried to obtain 71.2g of paracetamol, HPLC purity 99.99%, yield 82.69%.

[0042] Comparative Example 3

[0043] The method for treating unqualified paracetamol particles is the same as that in Example 1, except that sodium bisulfite is not added. The paracetamol HPLC purity is 99.59% and the content of the impurity para-aminophenol is 0.005% in the related substance detection index, which has the risk of exceeding the limit.

[0044] It is not difficult to see from the above embodiments 1-3 that under the protection of reducing agent, the substandard particles are first heated and dissolved, and then the upper liquid and the lower solid are separated by cooling and decantation. After the upper liquid is left to stand and the lower solid is separated, it is combined with the previous lower solid and repeatedly heated, and activated carbon is added for decolorization, and high-purity acetaminophen recovery products can be obtained by filtration and cooling crystallization, and the recovery rate is more than 92%. Limited by the influence of heating and dissolving the particles, pregelatinized starch, sodium carboxymethyl starch, and starch are gelatinized, which restricts the mode of adopting ordinary filtration, so comparative example 1 cannot be smoothly filtered by ordinary means. It is not difficult to see in comparative example 2 that there is still a certain amount of acetaminophen in the upper liquid of the first heating, so the recovery rate decreases. Comparative example 3 does not add a reducing protective agent, and the purity of the acetaminophen product liquid phase is reduced, wherein the content of aminophenol is larger, and there is a risk of over-limit. It can be seen from the above examples that the recovery of acetaminophen can be fully realized by adopting the water dissolution method, avoiding the defect of increased cost caused by using the organic solvent (ethanol), and has significant industrial application prospects.

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

Claims

1. A method for recovering acetaminophen, characterized in that the steps include: S1. Add unqualified acetaminophen particles and a first reducing agent to water, heat to 95-100° C. under stirring to dissolve for 0.5-1h, cool to stand, and decant to separate to obtain a first clear liquid and a first solid; the mass ratio of unqualified acetaminophen particles to water is (3.5-5):1; S2. The first clear liquid is allowed to stand until it is stable, and the second solid is obtained by decantation separation; S3. Add the second reducing agent and water to the first solid and the second solid, heat to 95-100°C with stirring to fully dissolve, add charcoal for decolorization, filter, cool the filtrate for crystallization, filter, and dry to obtain acetaminophen; the mass ratio of the total solid to water during the dissolution process is (3-4):

1.

2. The method according to claim 1, characterized in that: The unqualified acetaminophen particles include starch, pregelatinized starch, sodium carboxymethyl starch, thiourea, acetaminophen, magnesium stearate, and hydroxypropyl cellulose, and the acetaminophen content is less than 90%.

3. The method according to claim 1, characterized in that The first reducing agent and / or the second reducing agent are each independently selected from at least one of sodium bisulfite and sodium pyrosulfite.

4. The method according to claim 1, characterized in that: In step S1, the cooling and standing condition is 1-5°C for 1-2h.

5. The method according to claim 1, characterized in that In step S2, the standing condition is 5-10° C. for 12-24 hours.

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

7. The method according to claim 1, characterized in that In step S3, the filtrate is cooled and crystallized at 0-5°C for 2-5h.

8. Paracetamol obtained by the method according to any one of claims 1 to 7, characterized in that: Its purity is greater than 99.98%.

9. The use of acetaminophen according to claim 8, characterized in that: The use includes at least one of the following: a) Auxiliary agents for dye industry; b) Pesticide synthesis intermediates; c) Developer for medical X-ray films; d) Anti-aging agent for rubber products.

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