JPS6323985B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing amino acid salt crystals of acetylsalicylic acid, and more specifically, a method in which alcohol or an aqueous solution thereof or acetone or an aqueous solution thereof is used as a reaction and crystallization solvent, in which aromatic The present invention relates to a method for producing amino acid salt crystals of acetylsalicylic acid with good crystallinity and workability, characterized by the coexistence of group hydrocarbons.

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, aspirin has low solubility in gastric fluid, so when it is orally administered, it is absorbed slowly in the body, and during this period it is hydrolyzed in the gastric or intestinal secretions, resulting in undesirable effects.

Therefore, methods of increasing the absorption rate of aspirin by adding a buffer or solubilizing agent to aspirin have been proposed and are known. However, although it has been recognized that aspirin compositions to which such buffering agents have been added according to conventionally known techniques increase the dissolution rate, they are not always satisfactory, as they tend to cause constipation, laxative effects, and acid reaction, for example. . In order to improve these points, water-soluble addition salts of aspirin and basic amino acids have been proposed and are known, but these water-soluble addition salt preparations are also subject to hydrolysis by gastric or intestinal secretions when administered orally. Therefore, in order to avoid this problem, it has been proposed and known (for example, Japanese Patent Publication No. 53-8769) to make an injection of water-soluble addition salts of aspirin and basic amino acids, especially essential amino acids, and it is known that it is useful. It is attracting attention as a drug.

However, aspirin itself is a relatively unstable compound with respect to moisture and is susceptible to hydrolysis, and addition salts with basic amino acids have poor stability with respect to moisture and heat, so their industrial production is difficult. Many technical problems are raised to be solved. That is, addition salts of aspirin and basic amino acids are quite unstable, especially in water or aqueous solvents, and in such aqueous solutions, e.g.
By keeping it at a gentle temperature of 40-50℃ for a short time,
Most of it decomposes and is no longer recoverable. Moreover, such a water-containing solution state must be handled in a short time during production even at room temperature. High purity product (crystals) especially suitable for sterile injectable preparations
In order to obtain this, workability must be good. For example, it is extremely important that crystallization occurs quickly; if excessively long time is required due to poor crystallization, hydrolysis progresses and the purity of the product decreases. Furthermore, the turbulence during crystal washing must be quick for the same reason as above.

Also, due to the instability of the product, drying of the product crystals, which are wetted by the aqueous solvent system, must also be rapid.

However, conventionally known manufacturing methods do not necessarily satisfy these points. For example, when using alcohols such as methanol, ethanol, and isopropanol, acetone, ether, formamide, etc. alone or in a mixed solvent system, or a mixed solvent system of these solvents and water, the crystals obtained may be extremely fine or crystalline. The permeability of the product and the permeability during washing are extremely poor and require a long time, and the crystal adhering mother liquor is not easily cut, resulting in a decrease in the purity of the product and a long time required for drying. There are many problems that need to be resolved, such as the product becoming a hard lump and requiring a pulverization process to make it into an injectable solution at the time of use.However, in the past, when producing aspirin amino acid salts, there was no knowledge of the effects of solvents during crystallization. It has not been done.

Therefore, as a result of various studies in order to improve the above-mentioned difficulties, the inventors of the present invention have found that by coexisting an appropriate amount of an aromatic hydrocarbon in the alcohol or its aqueous solution or acetone or its aqueous solution used for the reaction and crystallization, a completely unexpected result has been discovered. The present invention was completed based on the discovery that not only the workability of filtering and drying is significantly improved, but also that an amino acid salt of aspirin with good crystallization can be obtained.

In an embodiment of the present invention, amino acids are used in aqueous solution or crystalline form. Examples of amino acids include dl-lysine, l-lysine, dl-arginine, l-arginine, histidine, and creatinine. If the purpose is to manufacture a sterile injectable preparation, the amino acid aqueous solution must be sterilized before use. When producing oral preparations, sterilization is not necessary and the amino acids can be used in the crystalline state.

On the other hand, aspirin is used after being dissolved in alcohol or acetone. When used as an injection, it is sterilized as described above. As the alcohol, methanol, ethanol, normal propanol, isopropanol, etc. are used. Among them, ethanol is preferred. The reaction between aspirin and an amino acid (hereinafter referred to as salt formation) is carried out by adding an aqueous solution of an amino acid or an amino acid crystal to the alcohol or acetone solution of aspirin and stirring the mixture. This mixing procedure can also be carried out by adding an alcoholic or acetone solution of aspirin to the aqueous amino acid solution, but the former gives more preferable results. Good results are obtained when the salt formation temperature is below room temperature, especially below 10°C. Salt production time is completed in 0.5 to 3 hours.
When an amino acid aqueous solution is used, it is generally desirable that the solution be in a uniform state, although it depends on the concentration of the aqueous solution and the amount of alcohol or acetone used to dissolve aspirin. Next, the alcohol or acetone containing aromatic hydrocarbons is gradually added to the salt-forming solution while gently stirring, or the salt-forming solution is gently stirred into the alcohol or acetone containing aromatic hydrocarbons. Crystallization is carried out by a method such as adding gradually.
The timing and process of adding the aromatic hydrocarbons may be arbitrarily selected as long as the aromatic hydrocarbons coexist in the crystallization mixture during salt crystallization. In this way, aspirin amino acid salt crystals crystallize and gradually increase in growth. The dropwise addition is carried out for 1 to 3 hours, depending on the manufacturing scale and other conditions, and then the mixture is gently stirred for ripening. The ripening time is 3
~6 hours is sufficient. It is also preferable to carry out this crystallization operation at a temperature of 10°C or lower.

As the alcohol used during crystallization, the above-mentioned alcohols may be used alone or as a mixture, but it goes without saying that from an industrial standpoint, it is preferable to use a single solvent in view of the solvent recovery operation.

The aromatic hydrocarbon coexisting in the alcohol or acetone used during crystallization in the method of the present invention is benzene or lower alkylbenzene,
As the lower alkylbenzene, toluene, ethylbenzene, isopropylbenzene, xylene, etc. are used. The amount to coexist is 0.1 to 10%, especially 2 to 5%, relative to alcohol or acetone.
(weight), a desirable effect can be obtained.

The crystals of aspirin amino acid salt crystallized by the method of the present invention have a specific gravity so large that they immediately settle as soon as stirring is stopped (in the case of conventional methods, the crystals are fine and difficult to settle), and the crystals can be filtered and washed easily. Because it is quick and has good crystallinity, the amount of mother liquor attached is small, and the solvent and water can be quickly removed at low temperatures during drying. An excellent product with good particle size, fluidity, bulk specific gravity, etc. can be obtained.

Next, examples and comparative examples of the present invention will be described in detail.

Example 1 37.8 g (0.210 mol) of aspirin was mixed with 5 benzene.
% (weight, same below) containing ethyl alcohol 200
The solution was stirred and dissolved in 1.5 ml of sterilized water, and sterilized at room temperature using a sterilized membrane filter.

29.3 g (0.200 mol) of dl-lysine (hereinafter abbreviated as dl-) was dissolved in 188 ml of pure water, stirred for a while, and then sterilized using the same membrane filter as above.

The above-mentioned aspirin ethyl alcohol solution was placed in a reaction vessel that had been cleaned in a sterile condition, and cooled from the outside to 0 to 5°C while being gently stirred. The above lysine aqueous solution was gradually dropped into this. During the dropwise addition, the internal temperature was kept at 0 to 5°C, and the solution was added dropwise for about 30 minutes, and the salt formation reaction was completed by stirring at the same temperature for about 30 minutes.
(Hereinafter, this will be referred to as a salt-forming solution).

1200 ml of ethyl alcohol containing 5% benzene, which had been sterilized in advance, was placed in a container that had been cleaned under aseptic conditions, and the above salt-forming solution was gradually added dropwise while stirring gently. The internal temperature was maintained at 0 to 5°C, and the dropwise addition took about 1 hour. After starting to drip the salt-forming solution,
Crystals began to precipitate after about 0.5 hours and were observed to gradually grow. 0 after finishing dripping
Crystallization (hereinafter referred to as crystallization operation) was completed by gently stirring at ~5°C for 4 hours.

Crystals were absorbed and filtered using a porcelain Buchner filter (diameter 140 mm) in a clean bench (clarity level 100). The time required was approximately 50 seconds. Furthermore, it was washed twice with 50 ml of sterilized ethyl alcohol. The time required for cleaning was approximately 30 seconds. The crystals were transferred to a vacuum dryer and dried at room temperature for about 12 hours under reduced pressure with a slight flow of nitrogen gas to obtain crystals of aspirin-lysine salt. The yield was 59 g, yield 90.2% (based on lysine), and melting point 138-139°C.

In this example, filtering and washing of the aspirin-lysine salt crystals was extremely rapid. Furthermore, no formation of lumps (consolidation) due to mutual adhesion of crystals was observed during drying, and a product with good fluidity was obtained.

Example 2 37.8 g (0.210 mol) of aspirin was stirred and dissolved in 150 g of acetone containing 5% toluene.
Sterilization was performed at room temperature using a membrane filter.

On the other hand, 29.3 g (0.200 mol) of lysine was dissolved in 226 ml of pure water, stirred for a while, and then sterilized using a membrane filter at room temperature.

Next, a salt-forming reaction was carried out in the same manner as described in Example 1 to obtain a salt-forming solution.

1,120 g of acetone containing 5% toluene, which had been sterilized in advance, was placed in a sterile-cleaned vessel, and the above salt-forming solution was gradually added dropwise while stirring gently.

Thereafter, the crystallization operation, crystal filtration and washing were carried out in the same manner as described in Example 1. The time required for crystallization was approximately 4 minutes, and the time required for washing was 3 minutes.

The crystals were dried in the same manner as described in Example 1 to obtain aspirin-lysine salt. Yield 61.2g, yield
93.5%, melting point 138-139°C.

In this example, the aspirin-lysine salt crystals were filtered and washed quickly. Further, during drying, no formation of lumps due to adhesion and aggregation between crystals was observed, and the fluidity was good.

Example 3 The same procedure as in Example 1 was carried out except that the benzene 5% ethyl alcohol content was replaced with benzene 2.5% ethyl alcohol. The yield of aspirin-lysine salt was 58.0 g, with a yield of 89.9%. The crystals developed rapidly, and during drying, no lumps were observed due to adhesion between crystals, and the fluidity was good.

Example 4 The same procedure as in Example 1 was carried out except that ethyl alcohol containing 5% benzene was replaced with isopropyl alcohol containing 5% benzene. The yield of aspirin-lysine salt was 60.6 g, with a yield of 92.6%. The crystals developed rapidly, and during drying, there was hardly any formation of lumps due to adhesion between crystals, and the fluidity was good.

Example 5 37.8g (0.210mol) of aspirin was added to 5g of toluene.
The solution was dissolved in 158 g of ethyl alcohol containing 15% ethyl alcohol, and sterilized using a membrane filter.

101g of lysine aqueous solution [29.3g as lysine
(0.200 mol)] was added with 7.8 g of glycine, stirred, filtered through paper, and the liquid was further sterilized using a membrane filter.

The above-mentioned aspirin ethyl alcohol solution was placed in a reaction vessel that had been cleaned in a sterile condition, and cooled from the outside to 0 to 5°C while being gently stirred. The above lysine aqueous solution was gradually dropped into this. The following operation was carried out in the same manner as described in Example 1 to obtain aspirin-lysine salt. Yield 64.7g, yield
It was 98.9%.

In this example, the time required to aspirin-lysine crystals was about 1 minute, and the time required to wash the crystals was about 1 minute. Furthermore, no formation of lumps due to mutual adhesive bonding of crystals was observed during drying, and a product with good fluidity was obtained.

Comparative Example In Example 2, 150 g of acetone containing 5% toluene was used to dissolve 37.8 g (0.210 mol) of aspirin, and 150 g of pure acetone was used instead of 150 g of acetone containing 5% toluene.
% pure acetone instead of using 1120g of acetone
Salt formation, crystallization, filtering and drying operations were carried out in the same manner as described in Example 2 except that 1120 g was used. The time required to collect the crystallized aspirin-lysine salt was about 40 minutes, or the time required to wash the crystals was about 15 minutes, which was a longer time than in Example 2.
Further, during drying of the product, lumps were often formed due to mutual adhesion of crystals. The yield was 51 g, and the yield was 77.9%.

Claims (1)

[Claims] 1. A method for producing amino acid salt crystals of acetylsalicylic acid by reacting acetylsalicylic acid with an amino acid, using alcohol or an aqueous solution thereof, or acetone or an aqueous solution thereof as a reaction and crystallization solvent. A method for producing an amino acid salt crystal of acetylsalicylic acid, characterized by coexisting an aromatic hydrocarbon. 2. The method according to claim 1, wherein the aromatic hydrocarbon used is benzene or lower alkylbenzene. 3 The amount of aromatic hydrocarbon used is 0.1 to 10% (weight) based on alcohol or acetone.
The method according to claim 1. 4. The method according to claim 1, wherein the amino acid used is l-lysine, dl-lysine, l-arginine, dl-arginine, l-histidine, dl-histidine or creatinine. 5 The alcohol used is methyl alcohol,
The method according to claim 1, wherein ethyl alcohol, n-propyl alcohol or isopropyl alcohol is used.