JPS6366821B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying an amino acid salt of acetylsalicylic acid, and more specifically, the present invention relates to a method for purifying an amino acid salt of acetylsalicylic acid. The present invention relates to a method for purifying an amino acid salt of acetylsalicylic acid, which is characterized by adding acetylsalicylic acid as a liquid conditioner to the system to prevent decomposition by coexisting with the system.

Acetylsalicylic acid (hereinafter referred to as aspirin)
is a drug with a long history and is recognized to be a useful analgesic, antipyretic, and antirheumatic agent when administered orally. On the other hand, it is known that aspirin has low solubility in gastric fluid, so when it is orally administered, it is absorbed slowly in the body, and during that time it undergoes hydrolysis in gastric or intestinal secretions, resulting in undesirable effects.

Therefore, methods of increasing the absorption rate of aspirin by adding a buffer or a solubilizing agent to aspirin have been proposed and are well known. However, although it has been recognized that aspirin compositions with the addition of such buffering agents or increasing the dissolution rate according to the known techniques, on the other hand, they are not always satisfactory due to their tendency to produce laxative effects, laxative effects, or acid reactions. The desired results have not been achieved.

In order to improve these points, water-soluble salts of aspirin and basic organic compounds, especially basic amino acids, have been proposed and are known, but these water-soluble addition salt preparations are also hydrated by gastric or intestinal secretions when administered orally. In order to avoid this problem, it has been proposed and known (e.g., Japanese Patent Publication No. 8769/1987) to make a water-soluble addition salt of aspirin and a basic amino acid into an injection, and it is useful. It is attracting attention as a drug.

However, aspirin itself is originally water,
Particularly in alkaline conditions, it is a compound that is relatively unstable against moisture and susceptible to hydrolysis, and therefore addition salts with basic amino acids are also relatively unstable against moisture and heat, so industrial production is difficult. poses many technical problems to be solved. In order to produce highly pure products that are particularly suitable for sterile injectable preparations, advanced technology and careful work management are required. However, even if products are manufactured using advanced technology and careful work management, not all products will pass the strict quality standards. Sometimes products that do not meet the specifications are obtained, and such so-called rejected products naturally require refining.

However, to date, there is no known technology for purifying the salts of aspirin and basic amino acids, especially the salts of aspirin and basic organic compounds.

Therefore, the present inventors have conducted various studies on purification methods and have completed the present invention.

Among the conventionally known organic bases of aspirin and basic amino acids, the salts of aspirin and basic amino acids can be used in most organic solvents, such as alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, and butyl alcohol, acetone, methyl ethyl ketone, and dioxane. Even when heated, it is insoluble or extremely sparingly soluble in industrial organic solvents such as organic solvents such as , tetrahydrofuran, and aromatic solvents such as benzene and toluene. Therefore, purification by the so-called recrystallization method, which is usually carried out by heating, dissolving in a solvent, cooling and crystallizing, cannot be applied in this case. Furthermore, the solubility in special solvents such as dimethylformamide, formamide, and acetamide is also unfavorable, and when such solvents are used, it is extremely difficult to remove the solvent that has adhered or occluded to the product, so it is difficult to use injectables. Not suitable for manufacturing.

The present inventors conducted research to develop a purification method based on the current situation, and first investigated a purification method using a so-called recrystallization method using a mixed solvent of a water-soluble organic solvent and water. As the solvent, use the above-mentioned organic solvents, water-soluble alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, and n-propyl alcohol, or ketones such as acetone, and dilute these solvents with an appropriate amount of water. We investigated using However, in this purification method by so-called recrystallization using a solvent, it is usually heated to dissolve the liquid, decolorize it using activated carbon if necessary, and cool the liquid to crystallize the crystals. It has been found that relatively unstable basic organic compound salts of aspirin, especially basic amino acid salts, decompose when heated and dissolved, resulting in a decrease in purity. For example, when the DL-lysine salt of aspirin is dissolved in 70-95% (by weight) dilute ethyl alcohol by heating (40-60°C) and then cooling (-5°C), there are almost no crystals. No precipitation occurred and the purpose of purification could not be achieved. Even when diluted acetone was used, the results were similar to those obtained when diluted alcohol was used.

Therefore, the present inventors first dissolved the basic amino acid salt of aspirin in pure water, decolorized and sterilized it if necessary, and gradually added the above-mentioned solvent such as alcohol or acetone to this solution to obtain an appropriate concentration. We conducted a study on the idea that if we adopt a method of preparing and cooling crystals, it would be possible to purify it without requiring heating and avoiding decomposition due to heating.
However, it was found that even with this method, sufficient purification results could not be obtained. For example, if aspirin DL-lysine salt (crude product) is dissolved in water at room temperature or cold, the sterilized solution is gradually dropped into ethyl alcohol or acetone cooled to 5°C while stirring, and aspirin DL-lysine is dissolved. Salt crystals crystallize. When this is filtered, washed with alcohol or acetone, and dried under reduced pressure under a nitrogen stream, a considerable amount of salicylic acid (free salicylic acid, salicylic acid DL-lysine salt, etc.) is still contained in the purified product, and purification by this method is found. was also not satisfactory.

After investigating the cause of this, we found that aspirin
When DL-lysine salt is dissolved in water, the pH of the aqueous solution is closely related to the stability of aspirin-DL-lysine salt. It was found that it is stable on the weakly acidic side. Therefore, it was thought that the above-mentioned decomposition could be avoided by adding an appropriate liquid conditioner and purifying the solution while keeping it on the weakly acidic side. As reagents that can be prepared on the acidic side, the use of inorganic acids such as sulfuric acid and hydrochloric acid, and organic acids such as acetic acid can be considered, but the addition of these acids causes re-decomposition because they are stronger acids than aspirin. This is undesirable, and especially when the product is a pharmaceutical, especially an injection, contamination with sulfate ions and chloride ions must be avoided. The present inventors searched for various liquid property regulators and surprisingly found that the addition of a small amount of aspirin was extremely effective in preventing decomposition, leading to the completion of the present invention.

The embodiments of the present invention will be described below. The solvent used for purification is suitably a water-soluble organic solvent.
Industrially useful solvents include methyl alcohol,
Examples include ethyl alcohol, isopropyl alcohol, normal propyl alcohol, and acetone, and among them, ethyl alcohol or acetone is preferably selected. Aspirin and a salt of a basic amino acid, such as the DL-lysine salt of aspirin, are first dissolved in pure water, and at the same time aspirin is added and stirred to dissolve. It is sufficient that the amount of aspirin added is 0.1 to 5% (weight unit, same hereinafter) based on aspirin-DL-lysine salt. Aspirin may be added in the form of a powder, or, if necessary, dissolved in alcohol or acetone. The pH of the dissolving solution is preferably 4 to 6.5, and the temperature is between 0° and 25°C. If decolorization and sterilization are required, decolorizing charcoal is added to this solution and filtered, and further sterilization is performed using a membrane filter.

The solution thus obtained is gradually dropped into alcohol or acetone while stirring gently. The temperature is 0° to 25°C, preferably 5° to 10°C. Eventually, aspirin's DL-lysine salt crystallizes out. After sufficient crystallization at 5° to 10°C, it is filtered, washed with dilute alcohol or dilute acetone, and dried under reduced pressure in a nitrogen stream at room temperature and then at around 40°C to obtain a purified product. The solvent concentration at the time of crystallization is set to an appropriate solvent concentration because when the water concentration is high, the amount of crystallization will naturally be small due to solubility. For example, when using alcohol or acetone, the concentration is 65% or more, preferably 75% to 95%. It is desirable that the concentration of the washing solvent be the same as that used during crystallization, and then washing with a high concentration solvent.

Prior to completing the present invention, a purification method using a conventional organic solvent such as dipping and stirring in alcohols, ethers, acetone, dioxane, tetrahydrofuran, benzene, etc., followed by further washing with these solvents was also proposed. However, a satisfactory purification effect could not be obtained. Furthermore, when hot immersion treatment was performed in these solvents, the purity was reduced due to decomposition.

The method of the present invention will be explained below with reference to Examples and Comparative Examples of the present invention.

Example 1 Aspirin-DL in a stirrer flask
- Lysine salt (purity 96.18%, salicylic acid content 0.52%,
Water 0.35%) 30g, pure water 60ml, powdered aspirin 1.6g and ethyl alcohol (concentration 94%) 15
ml and stirred at 10° to 15°C to dissolve. This solution was added dropwise to 590 ml of ethyl alcohol (concentration 94%) pre-cooled to 5° to 10° C. over a period of about 30 minutes while stirring gently. The mixture was gently stirred at 5 to 10° C. for about 4 hours to sufficiently crystallize aspirin-DL-lysine salt, then filtered under suction and washed three times with 20 ml of ethyl alcohol (concentration 94%).
The crystals thus obtained were dried under reduced pressure under a gentle nitrogen stream at room temperature and then at 40°C to obtain purified aspirin.
DL-lysine salt was obtained. Yield 26.0g, purification yield 86.7
%, purity of purified product 99.17%, salicylic acid content 0.10%,
The water content was 0.33%.

Example 2 In a flask with a stirrer, 43 ml of water, 1.1 g of aspirin, and aspirin-DL-lysine salt (purity 92.57).
%, salicylic acid content 4.40%, moisture 0.53%) and 16 ml of ethyl alcohol (concentration 94%).
The mixture was stirred at 10° to 15°C for 30 minutes to dissolve. The pH of this solution was 5.5. The mixture was decolorized by adding 0.5 g of activated carbon, and further sterilized using a membrane filter (TM-2p manufactured by Toyo Shisha Co., Ltd., 0.45μ, size 47m/m). This liquid is sterilized in advance and 3~
Ethyl alcohol (94% concentration) cooled to 5℃
The solution was added dropwise to 422 ml over about 30 minutes while stirring gently. Further, the mixture was gently stirred at the same temperature for about 4 hours to sufficiently crystallize aspirin-DL-lysine salt crystals. Purified aspirin was washed and dried in the same manner as described in Example 1.
DL-lysine salt was obtained. Yield 17.0g, purification yield 79.0
%, purity of purified product 98.58%, salicylic acid content 0.50%,
The water content was 0.25%. The product's sterility test (Japanese Antibiotic Pharmaceutical Standards, membrane filter method) results were negative for both bacteria and fungi. It was also negative in the progel method and the pyrodiene test using rabbits.

Example 3 In a flask with a stirrer, 60 ml of pure water, 1.0 g of aspirin, and aspirin-DL-lysine salt (purity
96.18%, salicylic acid 0.52%, water 0.35%) 30g
Add 20 ml of acetone and stir at 10° to 15°C to dissolve. This solution was decolorized by adding 0.5 g of activated carbon, and further sterilized using a membrane filter (see Example 2). Acetone 510, which has been sterilized and cooled to 5 to 10 degrees Celsius,
It took about 30 minutes to add the mixture dropwise into the ml solution while stirring gently. Further, the mixture was gently stirred at the same temperature for about 4 hours to sufficiently crystallize aspirin-DL-lysine salt crystals. Filtration, washing (acetone) and drying were carried out in the same manner as described in Example 1 to obtain purified aspirin-DL-lysine salt. Yield 25g, purification yield 83.3%, purity of purified product 98.70%,
The salicylic acid content was 0.20% and the water content was 0.25%. The product sterility test (see Example 2) and pyrodiene test results were both negative.

Comparative Example 1 In a flask with a stirrer and a reflux condenser,
Acetone (special grade reagent) 80ml and aspirin
DL-lysine salt (purity 95.86%, salicylic acid content)
0.87%, moisture 0.50%) was added, the inside of the flask was purged with nitrogen, and the mixture was stirred at reflux temperature (55-56°C) for 3 hours to elute impurities. The crystals were cooled to room temperature and separated, washed twice with 20 ml of acetone, and dried in the same manner as in Example 1. Obtained aspirin-DL
- 14.6g of lysine salt, pale yellow in color, purity
On the contrary, the purity decreased and the salicylic acid content increased to 80.5%, salicylic acid content 4.2%, moisture 0.50%, and others (14.8%).

Comparative Example 2 In a flask with a stirrer, 150 ml of isopropyl ether (special grade reagent) and aspirin-DL
- 50g of lysine salt (salicylic acid content 2.90%, moisture 0.50%) was added and stirred at room temperature for 1 hour. Strain the crystals and add 50ml of isopropyl alcohol.
The sample was washed three times with water and dried in the same manner as in Example 1. The salicylic acid content in the obtained aspirin-DL-lysine salt was 2.6%, which hardly decreased. The product thus obtained was treated once again with 150 ml of isopropyl ether in the same manner as above, but the content of salicylic acid in the product was 2.5%, which hardly decreased.

Comparative Example 3 In Example 2, crude aspirin-DL-lysine salt (purity 92.57%, salicylic acid content 4.40%, water content
The pH of the solution in this case was 7.5.The pH of the solution was 7.5. Aspirin
The yield of DL-lysine salt was 13 g, the product purity was 85.7%, the salicylic acid content was 5.50%, and the water was 0.30%, the purity decreased and the salicylic acid content increased on the contrary.

Claims (1)

[Scope of Claims] 1. When a basic amino acid salt of acetylsalicylic acid is purified using a solvent, acetylsalicylic acid is added as a pH adjusting agent and dissolved in an aqueous medium maintained under weak acidity. A method for purifying a basic amino acid salt of acetylsalicylic acid, which is then separated by cooling and crystallizing in an alcohol or hydrous alcohol, or acetone or hydrous acetone solvent. 2. The method according to claim 1, wherein the amount of acetylsalicylic acid added is such that the pH of the solvent system during purification is adjusted to PH4 to 6.5. 3 The basic amino acid salt of acetylsalicylic acid is
acetylsalicylic acid and dl-lysine, l-lysine,
The method according to claim 1, wherein the salt is a salt with dl-arginine, l-arginine, dl-histidine, l-histidine or creatinine. 4 The alcohol used is methyl alcohol,
The method according to claim 1, wherein ethyl alcohol, n-propyl alcohol or isopropyl alcohol is used.