JP3755908B2 - Crystallization of cephalosporin compounds - Google Patents

Description

上記の表から明らかなように、本発明方法により得られた結晶は、比表面積が１０⁴cm²／g未満であり、製剤化するのに望ましい結晶形（集合晶）を形成しており、従来方法で得られた結晶に比較して極めて操作性がよい。
【００３５】
【発明の効果】
本発明方法によれば、原料の由来、製造方法、不純物の有無や種類、含有量の違いに関係なく、粗または精製セファロスポリン化合物より一定以上の大きさの優れた結晶を得ることができる。そのような結晶は、圧縮率が小さく、流動性、充填性、耐圧性に優れ、錠剤用又はカプセル剤充てん用の原料として極めて操作性が高く、製剤効率並びに製品の品質の向上に寄与する。[0001]
[Industrial application fields]
The present invention relates to a method for crystallizing a cephalosporin compound and is used in the field of pharmaceutical production.
[0002]
[Prior art]
Oral cephalosporin preparations are usually provided as capsules, but the entire operation including separation, purification, drying, and filling of capsules is carried out smoothly to stabilize the quality. Obtaining such a preparation is important not only in terms of production efficiency, but also in ensuring reliability in terms of treatment. It has been found that the operability of the crystal and size (specific surface area) of the cephalosporin compound is extremely large. In other words, a uniform crystal aggregate having a specific surface area has a small compressibility and excellent fluidity, filling properties, and pressure resistance, and it passes through all processes from the production stage such as filtration and drying to capsule filling. Good operability.
[0003]
Conventionally, as a method for crystallizing a hydrochloride hydrate of a cephalosporin compound, a method of treating an alkali metal salt aqueous solution or an organic solvent solution of a cephalosporin compound with hydrochloric acid has been disclosed (JP-A-6-92970). In addition, a technique for changing the crystal form and crystal grain size by adding a small amount of a crystallizing agent in a crystallization operation is known. For example, a crystal for crystallization of an alkali metal salt of a cephalosporin compound is known. A method is also disclosed in which an amino acid or a compound having an amino group and a carboxyl group having a structure similar to that of the cephalosporin compound is used as an agent (Japanese Patent Laid-Open No. 4-247089).
[0004]
[Problems to be solved by the invention]
However, when the production method and quality of the cephalosporin compound are different, there is a problem that the shape and size of the crystal obtained by crystallization differ depending on the kind and amount of impurities contained. In addition, the above-mentioned publication using an amino acid or an analog thereof as a crystal clearing agent does not disclose application to an acid addition salt of a cephalosporin compound, and it is more efficient and applicable to an acid addition salt. The development of a good crystallization method has been desired.
[0005]
[Means for solving the problems]
The present invention solves the above problems, and even when the origin and quality of the raw materials are different, or even when the content of impurities that can also serve as a crystallizing agent is different, the cephalosporin compound and its salt have a constant crystal habit. Alternatively, the present invention provides a crystallization method capable of obtaining a salt hydrate crystal.
That is, the present invention provides a cephalospo which is characterized in that crystallization is performed in the presence of one or more kinds of crystallizing agents selected from the group consisting of water-soluble cellulose derivatives, water-soluble starch derivatives and polyvinyl compounds. A method for crystallizing a phosphorus compound is provided.
[0006]
As a result of analyzing the crystal obtained by the method of the present invention, it has formed an aggregate crystal having a specific surface area of 10 ⁴ cm ² / g or less, a small compressibility, excellent fluidity, filling property, pressure resistance, and operability. It became clear that it was extremely improved.
As a cephalosporin compound to which the crystallization method of the present invention can be applied, for example, 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamide] -3- ( 1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid (hereinafter abbreviated as S-1090; JP-A-5-059066) and its hydrochloride hydrate (JP-A-6-6 92970: 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy New Orleans, Louisiana 17-20, October 1993, Abstract No.416) Cefmenoxime, cefotetan, ceftazidime, cefazolin, cef Apilin, cephalothin, ceftorazole, cefamandol, cefoxitin, cefomethazole, cefuroxime, cefotaxime, cefoperazone, ceftizoxime, ceftriaxone, cefpimizole, cefpyramide, cefbuperazone, cefzonam, cefminox, cefodixefine, latamoxef Although salt hydrate is mentioned, it is not necessarily limited to these.
[0007]
The salts of the cephalosporin compound used in the method of the present invention include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and salts with inorganic acids such as hydrochloride and sulfate. An inorganic acid addition salt or a hydrate thereof is preferable.
Suitable compounds include S-1090, cefaclor, cephatridine, cephadroxyl, cephalexin, cefurazine, cefloxazine, cephaloridine, cefothiam, cefuroxime, cefixime, cefteram, cefpodoxime, cefmenoxime, cefotetan and ceftazidime and their hydrated acid addition salts or S-1090 monohydrochloride hydrate is particularly preferred.
[0008]
Examples of the crystallization agent that can be used in the crystallization method of the present invention include water-soluble cellulose derivatives, water-soluble starch derivatives, and polyvinyl compounds, and one or more compounds belonging to them are used. Specifically, as water-soluble cellulose derivatives, nonionic cellulose ethers such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose, and mixed nonions such as hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose Examples of water-soluble or polar organic solvent-soluble polyvinyl compounds include polyvinyl pyrrolidone, polyvinyl alcohol, and polyvinyl acetal diethylaminoacetate; examples of water-soluble starch derivatives include hydroxypropyl starch. Preferred crystallites are hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and polyvinylpyrrolidone.
[0009]
In the crystallization method of the present invention, first, for example, a cephalosporin compound to be crystallized or an acid addition salt thereof is dissolved in water, an organic solvent, or a mixture thereof, or a cephalosporin compound is suspended in water. Thereafter, for example, a base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate is added to dissolve the cephalosporin compound, and a solution of the cephalosporin compound is prepared. A known method may be employed as appropriate.
Crystallization is performed, for example, by one of the following methods. 1) In the presence of a crystallizing agent, 1) Water or an organic solvent is injected into a cephalosporin solution to cause direct crystallization. 2) The cephalosporin solution is poured into water or an organic solvent and directly crystallized.
[0010]
If necessary, any method known to those skilled in the art, for example, use of seed crystals, concentration, temperature adjustment, pH adjustment, etc. may be employed. The pH is adjusted by, for example, injecting an inorganic acid (hydrochloric acid, sulfuric acid, etc.) into the cephalosporin solution or injecting a cephalosporin solution into the inorganic acid. The crystallizer may be added to any of the solutions involved. That is, it is dissolved in either a cephalosporin solution, water for mixing or an organic solvent, or an inorganic acid such as hydrochloric acid or pH for adjusting pH.
Examples of the organic solvent used in the method of the present invention include conventional industrial organic solvents such as lower alcohols, ketones, nitriles, esters, etc., and methanol, ethanol, acetone, isopropyl alcohol, etc. are preferable. It is not limited. The solvent is used alone or as a mixed solvent of two or more.
[0011]
In the method of the present invention, in order to obtain an acid addition salt of a cephalosporin compound or a hydrate thereof, it is preferable to crystallize from an acidic aqueous solution which may contain an organic solvent. In one preferred embodiment, the acidic aqueous solution has a pH of about 6 or less. The addition amount of the crystallizing agent is about 0.005 to 5% by weight, preferably 0.1 to 2% by weight, based on the cephalosporin compound, and is appropriately adjusted depending on the target compound and the target crystal form. be able to. The crystallization temperature is usually about 0 to 90 ° C or under ice cooling, preferably 5 to 50 ° C. Under such conditions, it is allowed to stand or stir until the target crystal is crystallized.
[0012]
Crystallized crystals are separated by ordinary methods such as centrifugation, and are subjected to normal drying conditions such as heating, normal temperature, low temperature, pressurization, normal pressure, reduced pressure, ventilation, hot air, dehumidification with a desiccant, and fluidized drying. Use to dry. However, when obtaining a hydrate crystal, the drying condition is selected so that water molecules are not completely removed, or the dehydrated crystal is left under humidified conditions of, for example, a temperature of 10 to 30 ° C. and a humidity of 50 to 90%. The water may be absorbed again. The water content of the crystals obtained by the method of the present invention may vary depending on the substrate and is not necessarily limited. For example, in the case of S-1090, monohydrochloride monohydrate (water content) is obtained by ordinary drying. The rate tends to stabilize as about 3.1 to 6.3%). In addition, the specific surface area of the obtained hydrochloride hydrate crystals hardly changes within this water content range.
[0013]
【Example】
The present invention will be described in more detail with reference to examples below, but these do not limit the scope of the present invention.
Preparation crude S-1090 hydrochloride hydrate 7β - [(Z) -2- ( 2-t- butoxycarbonylamino-4-thiazolyl) -2-trityloxyiminoacetamido] -3- (1,2,3 26.0 g of triazol-5-ylthiomethyl thio) -3-cephem-4-carboxylic acid diphenylmethyl ester is suspended in a mixture of 270 ml of dichloromethane and 51 ml of anisole and stirred at 0 to 5 ° C., while containing aluminum chloride 17 After dropwise addition of 60 g of anisole 60 ml solution, the mixture is stirred for 1 hour 50 minutes. The resulting reaction solution containing S-1090 is poured into a mixed solution of 220 ml of methanol, 114 ml of water and 29.8 g of hydrochloric acid (stirring at 0 to 15 ° C.). The aqueous layer is separated, washed twice with 100 ml of dichloromethane, added with 30 mg of seed crystals, stirred at 20-28 ° C. for 1.5 hours, and concentrated under reduced pressure to about 150 ml. The crystallized crystals are taken and washed with 260 ml of water to obtain 24.5 g of crude S-1090 hydrochloride hydrate.
[0014]
Example 1
Into a solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example in 100 ml of methanol, 10 ml of an aqueous solution in which 0.03 g of hydroxypropylcellulose is dissolved is poured. This solution was poured into 360 ml of 3N hydrochloric acid kept at 40 ° C. over 30 minutes, and seed crystals were added on the way to crystallize S-1090 monohydrochloride hydrate.
The precipitated crystals were collected, washed with 80 ml of water, and dried by aeration at room temperature to obtain 8.3 g of white crystals of S-1090 hydrochloride hydrate.
[0015]
Example 2
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was carried out in the same manner as in Example 1 to obtain S-1090 hydrochloride water. 8.5 g of white crystals of the Japanese product was obtained.
[0016]
Example 3
To a solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example 1 and 0.03 g of polyvinylpyrrolidone in 160 ml of methanol was added 100 ml of 0.5N hydrochloric acid, seed crystals were added, and the mixture was concentrated under reduced pressure. S-1090 hydrochloride hydrate was crystallized. The precipitated crystals were taken, washed with 80 ml of water, and dried to obtain 9.0 g of white crystals of S-1090 hydrochloride hydrate.
[0017]
Example 4
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was performed in the same manner as in Example 3 to obtain S-1090 hydrochloride water. 9.0 g of a pale yellow crystal of the Japanese product was obtained.
[0018]
Example 5
10 g of crude S-1090 hydrochloride hydrate obtained in the production example was suspended in water and dissolved by adding IN sodium hydroxide solution to 250 ml of an aqueous solution of S-1090 sodium salt to obtain 0.03 g of hydroxypropylcellulose. Dissolve. This solution was poured into 360 ml of 3N hydrochloric acid at 40 ° C. as in Example 1, and seed crystals were added on the way to crystallize S-1090 hydrochloride hydrate.
The precipitated crystals were collected, washed with 80 ml of water and dried to obtain 8.5 g of white crystals of S-1090 hydrochloride hydrate.
[0019]
Example 6
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was performed in the same manner as in Example 5 to obtain S-1090 hydrochloride water. 8.4 g of white crystals of the Japanese product was obtained.
[0020]
Example 7
After 10 g of crude S-1090 hydrochloride hydrate was suspended in water, hydrochloric acid was added to 250 ml of an aqueous solution of S-1090 sodium salt obtained by dissolving by adding IN sodium hydroxide aqueous solution to pH 4. Dissolve 0.03 g of propylcellulose. This solution was poured into 200 ml of 6N hydrochloric acid at 40 ° C. as in Example 1, and seed crystals were added on the way to crystallize S-1090 hydrochloride hydrate. The crystallizing crystals were taken, washed with 80 ml of water and dried to obtain 8.3 g of white crystals of S-1090 hydrochloride hydrate.
[0021]
Example 8
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was performed in the same manner as in Example 7 to obtain S-1090 hydrochloride water. 8.5 g of white crystals of the Japanese product was obtained.
[0022]
Example 9
10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing the crude S-1090 obtained in the production example once from aqueous hydrochloric acid was suspended in water, and then dissolved by adding IN sodium hydroxide aqueous solution. Hydrochloric acid is added to 250 ml of an aqueous S-1090 sodium salt solution to adjust the pH to 4, and 0.015 g of hydroxypropylmethylcellulose is dissolved in this solution. This solution was poured into 200 ml of 6N hydrochloric acid in the same manner as in Example 1, and seed crystals were added along the way to crystallize S-1090 hydrochloride hydrate. The crystallized crystals were collected, washed with 80 ml of water and dried to obtain 8.5 g of white crystals of S-1090 hydrochloride hydrate.
[0023]
Example 10
In the same manner as in Example 9, 10 g of purified S-1090 hydrochloride hydrate which had been recrystallized once was suspended in water and then dissolved by adding IN sodium hydroxide aqueous solution to obtain 250 ml of an aqueous S-1090 sodium salt solution. Hydrochloric acid was added to adjust the pH to 4, and this solution was poured into 200 ml (40 ° C.) of 6N hydrochloric acid in which 0.03 g of hydroxypropylcellulose was dissolved, and seed crystals were added on the way to crystallize S-1090 hydrochloride hydrate. I let you. The crystallized crystals were collected, washed with 80 ml of water and dried to obtain 8.5 g of white crystals of S-1090 hydrochloride hydrate.
[0024]
Example 11
Crystallization operation was performed in the same manner as in Example 9 using 0.003 g of methylcellulose instead of hydroxypropylmethylcellulose to obtain 8.0 g of pale yellow crystals of S-1090 hydrochloride hydrate.
[0025]
Example 12
By using 0.005 g of polyvinylpyrrolidone instead of hydroxypropylmethylcellulose and performing the crystallization operation in the same manner as in Example 9, 8.0 g of pale yellow crystals of S-1090 hydrochloride hydrate were obtained.
In addition, the water content of each crystal after drying obtained in Examples 1 to 12 was in the range of about 3.0 to 3.5% by the Karl Fischer method.
[0026]
In the following comparative examples, the crystallization operation was performed under the same conditions as in the above examples without using a crystallization agent.
Comparative Example 1
A solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example in 100 ml of methanol was poured into 360 ml of 3N hydrochloric acid, seed crystals were added on the way, and S-1090 hydrochloride hydrate was crystallized. And dried to obtain 9.0 g of white crystals of S-1090 hydrochloride hydrate.
[0027]
Comparative Example 2
Instead of the crude S-1090 hydrochloride hydrate, 10 g of purified S-1090 hydrochloride hydrate once recrystallized from hydrochloric acid water was used, and the same crystallization operation as in Comparative Example 1 was performed. 8.7 g of white crystals of hydrochloride hydrate were obtained.
[0028]
Comparative Example 3
To a solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example in 160 ml of methanol, 100 ml of 0.5N hydrochloric acid was added, seed crystals were added, and the mixture was concentrated under reduced pressure, and S-1090 hydrochloride water was added. The hydrate was crystallized and dried to obtain 8.2 g of pale yellow crystals of S-1090 hydrochloride hydrate.
[0029]
Comparative Example 4
Instead of the crude S-1090 hydrochloride hydrate, 10 g of purified S-1090 hydrochloride hydrate, which was once recrystallized from hydrochloric acid water, was used for the same crystallization operation as in Comparative Example 3, and S-1090 8.0 g of pale yellow crystals of hydrochloride hydrate was obtained.
[0030]
Comparative Example 5
250 ml of an aqueous S-1090 sodium salt solution obtained by dissolving 10 g of the crude S-1090 hydrochloride hydrate obtained in the production example was poured into 360 ml of 3N hydrochloric acid, seed crystals were added on the way, and S-1090 hydrochloride hydrated. The product was crystallized and dried to obtain 8.7 g of white crystals of S-1090 hydrochloride hydrate.
[0031]
Comparative Example 6
Using 10 g of purified S-1090 hydrochloride hydrate that had been recrystallized once and containing about 1% of impurities, the same crystallization operation as in Comparative Example 5 was carried out to obtain white crystals of S-1090 hydrochloride hydrate 8 0.8 g was obtained.
[0032]
Comparative Example 7
Hydrochloric acid was added to 250 ml of an aqueous S-1090 sodium salt solution obtained by dissolving 10 g of the crude S-1090 hydrochloride hydrate obtained in the production example to adjust the pH to 4, and this solution was poured into 200 ml of 6N hydrochloric acid. Was added to crystallize S-1090 hydrochloride hydrate and dried to obtain 8.9 g of white crystals of S-1090 hydrochloride hydrate.
[0033]
Comparative Example 8
In place of the crude S-1090 hydrochloride hydrate, 10 g of purified S-1090 hydrochloride hydrate that had been recrystallized once was used, and the same crystallization operation as in Comparative Example 7 was performed to obtain S-1090 hydrochloride hydrate. Of white crystals was obtained.
The results of analyzing the S-1090 hydrochloride hydrate crystals obtained in the above Examples and Comparative Examples with a microscope and SSS method (sub-sieve cider method) are shown in a table.
[0034]
[Table 1]

As is clear from the above table, the crystal obtained by the method of the present invention has a specific surface area of less than 10 ⁴ cm ² / g and forms a crystal form (aggregate crystal) desirable for formulation, Compared with crystals obtained by conventional methods, the operability is very good.
[0035]
【The invention's effect】
According to the method of the present invention, it is possible to obtain crystals having a certain size or larger than the crude or purified cephalosporin compound regardless of the origin of the raw material, the production method, the presence or absence of impurities, the type, and the difference in content. . Such crystals have a small compressibility, excellent fluidity, filling properties, and pressure resistance, are extremely easy to operate as a raw material for tablets or capsules, and contribute to improvement in formulation efficiency and product quality.

Claims (9)

  A crystallization method of a cephalosporin compound, characterized by crystallization in the presence of a water-soluble cellulose derivative or a polyvinyl compound.   The method according to claim 1, wherein the cephalosporin compound is an acid addition salt or a hydrate thereof.   The method according to claim 1, wherein the cephalosporin compound is hydrochloride or a hydrate thereof.   The cephalosporin compound is 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3- (1,2,3-triazol-4-yl). The method according to claim 1, which is thiomethylthio-3-cephem-4-carboxylic acid monohydrochloride hydrate.   The method according to any one of claims 1 to 4, wherein crystallization is performed from an acidic aqueous solution which may contain an organic solvent.   The method according to claim 5, wherein the acidic aqueous solution has a pH of 6 or less.   The method according to any one of claims 1 to 6, wherein the crystal clearing agent is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and polyvinylpyrrolidone.   A cephalosporin compound crystal obtained by the method according to claim 1. The crystal according to claim 8, wherein the specific surface area is less than 10,000 cm ² / g.