CN1775784A - Purification method of ceftazidime - Google Patents

Abstract

The method relates to a method for purifying ceftazidime, more concretely relating to a method for preparing high quality ceftazidime pentahydrate by impure, high-polymer impurity content ceftazidime through crystallization. It prepares impure, high-polymer impurity content ceftazidime pentahydrate, ceftazidime Hcl, ceftazidime hydrobromide or ceftazidime overdue or recovered from the market, into a ceftazidime water solution, then regulates the pH value of the ceftazidime water solution to 1.5-2.5 by alkali or acid, here the impurity ceftazidime polymer is separated out with a little ceftazidime, and the separated-out matter is filtered, and the pH value of the filtrate is regulated to 3.5-4.8 by alkali so that the ceftazidime pentahydrate crystals are separated out. The method is simple and convenient to operate, low-cost, good-safety and high-yield. The obtained ceftazidime pentahydrate crystals are high purity and the polymer is low-content, reaching pharmacopoeia specified requirements.

Description

Purification method of ceftazidime

technical field

The present invention relates to a method for purifying ceftazime, in particular to a method for preparing high-quality ceftazime pentahydrate from impure ceftazime containing polymer impurities through crystallization.

Background technique

Ceftazidime pentahydrate is a cephalosporin widely used clinically, and its structural formula is as follows:

In order to ensure the safety of human medicine, the National Pharmacopoeia stipulates that for ceftazidime antibiotics, the content of ceftazidime pentahydrate is not less than 95%, the content of polymer is not more than 0.3%, and its color is not higher than No. 6 color. During storage, ceftazidime antibiotics tend to degrade and polymerize, especially when subjected to high temperature (>50°C), to form polymers such as ceftazidime dimers, trimers and polymers, which lead to the formation of active ingredients of the drug. The content is reduced, the color is strengthened, and the content of polymer impurities is increased. In addition, due to the long storage time of expired ceftazidime antibiotics, the content of active ingredients of the drug is often reduced, the color becomes darker, and the polymer content increases. Also, in some cases, due to improper control of the production process, the obtained ceftazime pentahydrate, ceftazime dimer, trimer and multipolymer, etc. have a particularly high content of polymers. When the polymer content is high, it is easy to cause allergic reactions in the human body. Therefore, for ceftazidime pentahydrate or ceftazime pharmaceutical preparations with high polymer impurity content, it is necessary to further purify to obtain high-quality, high-purity ceftazidime pentahydrate crystals.

GB2063871 discloses a method for preparing ceftazidime pentahydrate crystals. The method is to adjust the pH of ceftazidime salt or alkali salt solution to 3.3-4.0, so that ceftazidime pentahydrate crystals are precipitated. For ceftazidime pentahydrate or ceftazidime pharmaceutical preparations with higher polymer impurity content, for example, when the polymer impurity content is higher than 4%, crystallization and purification according to the method of GB2063871, the polymer impurity is often precipitated together with the ceftazidime pentahydrate crystal, Therefore, the content of polymer impurities in the obtained crystals of ceftazidime pentahydrate is still high.

GB2157682 discloses a method for recovering ceftazidime. The method is to use a non-functional macroporous network resin to contact with an aqueous solution of ceftazidime with a pH of 2.0 to 5.5, thereby absorbing ceftazidime, and then eluting to separate ceftazidime or its salt or its hydration. thing. According to this method, the final product may be ceftazidime or its salt or its hydrate, the content of impurity polymers is reduced, and the color of the product becomes lighter, but this method requires the use of non-functional macroporous network resin, followed by elution and separation. Many, complicated operation and high cost.

US4659813 discloses a method for preparing ceftazidime pentahydrate crystals, the method is, at a temperature of about 5-15 ° C, the pH of ceftazime aqueous solution is about 5.5-about 6.5, and the pH is adjusted to about 4.0-about 4.7 with acid , and by controlling the addition of acid during the crystallization process, the pH is maintained at about 4.0 to about 4.7, thereby separating out ceftazidime pentahydrate crystals. Although this method is helpful to improve product purity and reduce polymer content, for the ceftazidime preparation with very high polymer content and poor color, according to this method, high-quality ceftazidime pentahydrate crystals still cannot be obtained. Simultaneously, this method first dissolves material in the higher system of pH, causes ceftazidime to degrade to some extent, and the rate of recovery reduces like this.

Contents of the invention

Therefore, the object of the present invention is to provide a simple method for purifying ceftazime that can effectively remove polymer impurities for ceftazime with high content of impurity polymers, that is, a method for preparing high-quality ceftazime pentahydrate crystals.

The invention provides a method for purifying ceftazidime containing polymer impurities, the method comprising:

Add ceftazidime containing polymer impurities into water, optionally add an acid to dissolve it, and obtain an aqueous solution of ceftazidime; then use alkali or acid to adjust the pH of the aqueous solution of ceftazidime to 1.5 to 2.5, and precipitates are precipitated; filter to remove the precipitates, and the obtained filtrate Continue to use alkali to adjust the pH to 3.5-4.8, control the temperature at 0-40° C., and crystallize ceftazidime pentahydrate.

Ceftazime pentahydrate, ceftazime hydrochloride or ceftazime hydrobromide with high polymer content and expired or recovered ceftazime preparations from the market can be refined by the method of the present invention to obtain pure ceftazidime pentahydrate. For impure, polymer-containing ceftazime pentahydrate, disperse it in water, add acid to dissolve it, and obtain ceftazime aqueous solution; for impure, polymer-containing ceftazime hydrochloride or ceftazime hydrobromide, you can Dissolve directly in water to obtain ceftazidime aqueous solution; impure, polymer-containing ceftazidime preparations, such as ceftazidime containing sodium carbonate or ceftazidime containing arginine, can be directly dissolved in water to obtain ceftazidime aqueous solution. In the method of the present invention, the ceftazidime aqueous solution obtained in this way generally has a ceftazime content of 5wt.%-60wt.%, preferably 10wt.%-40wt.%.

Described polymer impurity is the mixture of polymers such as ceftazime dimer, trimer and multipolymer generated by ceftazime in the preparation and storage process, when the content of these polymer impurities in ceftazime is higher than 1wt. %, it is especially suitable for purification by the method of the present invention.

The acid used in the method of the present invention can be inorganic acid or organic acid, wherein said inorganic acid includes hydrochloric acid, phosphoric acid or sulfuric acid, preferably hydrochloric acid; said organic acid includes formic acid or acetic acid. The adding method of the acid is preferably dropwise under stirring.

The alkali used in the method of the present invention includes inorganic alkali or organic alkali, wherein said inorganic alkali includes sodium hydroxide solution, potassium hydroxide solution, sodium acetate, sodium isooctanoate or ammoniacal liquor etc.; Described organic alkali includes triethyl Amine or n-butylamine, etc. The adding method of the base is preferably dropwise under stirring.

In the purification method provided by the present invention, when the ceftazidime aqueous solution is prepared from ceftazidime containing polymer impurities, it is usually carried out at a temperature of 0-30°C. Then adjust the pH of ceftazidime aqueous solution with alkali or acid to be 1.5～2.5, now the polymer impurity basically all separates out, simultaneously with a small amount of ceftazidime (about 0.5%～2% of the ceftazime total amount in the solution) to separate out together, by Filtration to remove polymer impurities. The obtained filtrate after filtration is adjusted to pH 3.5～4.8 with alkali, preferably 4.0～4.6, at this moment ceftazidime pentahydrate crystal begins to separate out, crystallization temperature is controlled at 0～40 ℃, preferably 5～30 ℃, and at this temperature Stir or stand still to grow crystals for 1 to 10 hours. Then, after filtration, solvent washing and drying, ceftazidime pentahydrate crystals were obtained.

In the method for purifying ceftazime provided by the present invention, in order to obtain ceftazime pentahydrate crystals with good color and luster, it is preferable to add activated carbon to decolorize during the purification process, and the consumption of activated carbon is 2% to 30% of that of ceftazime containing polymer impurities (weight).

The advantages of the present invention are: the method of the present invention is especially suitable for the purification of ceftazime pentahydrate, amorphous ceftazime, ceftazidime salt or ceftazidime pharmaceutical preparations with high polymer impurity content, and the obtained ceftazime pentahydrate crystals after purification have high purity, The polymer content is low, for example, less than 0.2%, meeting the Pharmacopoeia requirements. The method is simple to operate, low in cost, good in safety and high in yield.

Detailed ways

In the present invention, according to the assay method stipulated in "Chinese Pharmacopoeia" (2000 edition, page 171 to page 172, Chemical Industry Press), adopt high performance liquid chromatography to measure the content of ceftazidime, according to column chromatography to measure ceftazime polymer The content of the following content is calculated according to the dry product according to "Chinese Pharmacopoeia" (2000 edition).

The following examples are provided to specifically illustrate the embodiments of the present invention, and these examples do not limit the scope of the present invention.

Example 1

For unqualified ceftazime pentahydrate, the content of ceftazime determined by high performance liquid chromatography is 90.1wt.%, and the content of polymer determined by illuminating column chromatography is 8.5wt.%.

Suspend 20.0 g of the unqualified ceftazidime pentahydrate in 100 ml of water, cool to 0-5° C. in an ice-water bath, and add 36 wt.% concentrated hydrochloric acid dropwise while stirring until the material dissolves to obtain an aqueous solution of ceftazidime. Under stirring condition, in the ceftazidime aqueous solution, dropwise add 2N NaOH solution, adjust pH to 2.5, separate out off-white precipitate, filter off precipitate (precipitate wet weight 1.99g, HPLC detection contains ceftazidime 0.25g), obtain filtrate. Then, the resulting filtrate was heated up to 5-10°C in an ice-water bath, and 2N NaOH solution was added dropwise with stirring to make the pH 4.0, ceftazidime pentahydrate crystals were precipitated, and the temperature was adjusted to 0-5°C in an ice-water bath. , stirring and growing the crystal for 8 hours. Thereafter, it was suction filtered, washed with 30 ml of water and then with 50 ml of acetone, drained, and vacuum-dried to obtain 16.0 g of ceftazidime pentahydrate. The molar yield is 87.9%, the content is 98.5wt%, the polymer is 0.08wt.%, and the drying weight loss is 14.0wt.%.

Example 2

20.0 g of the unqualified ceftazime pentahydrate of Example 1 was suspended in 100 ml of water, cooled to 0-5° C. with an ice-water bath, and 99 wt.% acetic acid was added dropwise while stirring until the material was dissolved to obtain a clarified aqueous solution of ceftazime. Then, 0.5 g of activated carbon was added to the obtained aqueous solution of ceftazidime, stirred and decolorized for 30 minutes, and then filtered to remove the activated carbon to obtain a filtrate. The resulting filtrate was kept in an ice-water bath to keep the temperature at 0-5°C. Under stirring, 22 wt.% ammonia water was added dropwise to adjust the pH to 2.0. An off-white precipitate was precipitated, and the precipitate was filtered off to obtain the filtrate. Then, the resulting filtrate was heated to 20-25°C in a water bath, and 22wt.% ammonia water was added dropwise under stirring, so that the pH was 4.2, and ceftazidime pentahydrate crystals were precipitated, and then the temperature was adjusted to 0-5°C in an ice-water bath. Crystal growth for 6 hours. Thereafter, it was suction filtered, washed with 30 ml of water and then 50 ml of acetone, drained, and vacuum-dried to obtain 15.0 g of ceftazidime pentahydrate. The molar yield is 83.2%, the content is 98.9wt.%, the polymer is 0.07wt.%, and the drying weight loss is 13.9wt.%.

Example 3

20.0 g of the unqualified ceftazime pentahydrate of Example 1 was suspended in 30 ml of water, cooled to 0-5° C. with an ice-water bath, and 36 wt.% hydrochloric acid was added dropwise while stirring until the material was dissolved to obtain a clarified aqueous solution of ceftazime. Then, 0.5 g of activated carbon was added to the obtained aqueous solution of ceftazidime, stirred and decolorized for 30 minutes, and then filtered to remove the activated carbon to obtain a filtrate. The resulting filtrate was kept in an ice-water bath to keep the temperature at 0-5°C. Under stirring, 22 wt.% ammonia water was added dropwise to adjust the pH to 2.0. An off-white precipitate was precipitated, and the precipitate was filtered off to obtain the filtrate. Then, the resulting filtrate is heated to 20-25°C in a water bath, and 22wt.% ammonia water is added dropwise under stirring, so that the pH is 3.8, and ceftazidime pentahydrate crystals are precipitated, and then the temperature is adjusted to 0-5°C in an ice-water bath. Crystal 4 hours. Thereafter, it was suction filtered, washed with 30 ml of water and then 50 ml of acetone, drained, and dried in vacuo to obtain 15.5 g of ceftazidime pentahydrate. The molar yield is 86.0%, the content is 98.8wt.%, the polymer is 0.08wt.%, and the weight loss on drying is 14.1wt.%.

Example 4

At a room temperature of 23° C., 20 g of unqualified ceftazime pentahydrate of Example 1 was suspended in 160 ml of water, and 36 wt.% hydrochloric acid was added dropwise while stirring until the material was dissolved to obtain a clear aqueous solution of ceftazidime. Add 1 g of activated carbon to the obtained ceftazidime aqueous solution, stir and decolorize for 15 minutes, then filter to remove the activated carbon to obtain a filtrate. The obtained filtrate was added dropwise with triethylamine under stirring to adjust the pH to 1.8, and an off-white precipitate was precipitated, which was filtered off to obtain a filtrate. Then, triethylamine was added dropwise to the obtained filtrate under stirring, so that the pH was 3.9, ceftazime pentahydrate crystals were precipitated, and then the temperature was adjusted to 0-5° C. in an ice-water bath, and the crystals were grown with stirring for 1 hour. Thereafter, it was suction filtered, washed with 30 ml of water and then with 50 ml of acetone, drained, and vacuum-dried to obtain 11.2 g of ceftazidime pentahydrate. The molar yield is 61.7%, the content is 98.5wt.%, the polymer is 0.1wt.%, and the loss on drying is 14.1wt.%.

Example 5

Suspend 20 g of the unqualified ceftazime pentahydrate of Example 1 in 40 ml of water, cool to 0-5° C. in an ice-water bath, and add 36 wt.% hydrochloric acid dropwise while stirring until the material dissolves to obtain a clarified aqueous solution of ceftazime. Then, 3 g of activated carbon was added to the obtained aqueous solution of ceftazidime, stirred and decolorized for 50 minutes, and then filtered to remove the activated carbon to obtain a filtrate. The obtained filtrate was kept at 10-15°C in a water bath, and 1.5N sodium acetate was added dropwise with stirring to adjust the pH to 2.0. An off-white precipitate was precipitated, and the precipitate was filtered off to obtain a filtrate. Then, adjust the temperature of the obtained filtrate to 10-15°C with a water bath, add 1.5N sodium acetate dropwise under stirring to make the pH 4.0, ceftazidime pentahydrate crystals are precipitated, and then adjust the temperature to 0-5°C with an ice-water bath Static crystal growth for 3 hours. Thereafter, it was suction filtered, washed with 30 ml of water and then with 50 ml of acetone, drained, and vacuum-dried to obtain 16.1 g of ceftazidime pentahydrate. The molar yield is 89.1%, the content is 98.0wt.%, the polymer is 0.12wt.%, and the weight loss on drying is 14.2wt.%.

Example 6

For unqualified ceftazime hydrochloride, the content of ceftazime determined by high performance liquid chromatography is 93.1wt.%, and the content of polymer determined by illuminating column chromatography is 5.5wt.%.

Add 20 g of the unqualified ceftazidime hydrochloride to 100 ml of water, and cool to 0-5° C. in an ice-water bath to obtain an aqueous solution of ceftazidime. Under stirring conditions, 8N sodium isooctanoate was added dropwise to the obtained ceftazidime aqueous solution to adjust the pH to 2.5, and an off-white precipitate was precipitated, which was filtered off to obtain a filtrate. Then, the obtained filtrate was kept at 0-5°C in an ice-water bath, and 8N sodium isooctanoate was added dropwise with stirring to make the pH 4.4, ceftazidime pentahydrate crystals were precipitated, and the crystals were grown statically for 5 hours. Then suction filter, first wash with 30ml of water, then with 50ml of acetone, drain, and vacuum-dry to obtain 15.0g of ceftazidime pentahydrate. The molar yield is 80.6%, the content is 99.2wt.%, the polymer is 0.1wt.%, and the weight loss on drying is 14.0wt.%.

Example 7

Unqualified ceftazidime preparations, the content of ceftazidime measured by high performance liquid chromatography is 81.5%, and the content of polymer measured by illuminating column chromatography is 5.5wt.%, sodium carbonate 10wt.% (according to USP XXIV edition 351 page measurement method).

Add 20 g of the unqualified ceftazidime preparation to 80 ml, dissolve, cool to 0-5° C. in an ice-water bath, and add 6N hydrochloric acid dropwise while stirring to adjust the pH to 1 to obtain an aqueous solution of ceftazidime. Under stirring conditions, 6N NaOH was added dropwise to the obtained aqueous solution of ceftazidime to adjust the pH to 2.4, an off-white precipitate was precipitated, and the precipitate was filtered off to obtain a filtrate. Then, the resulting filtrate was heated to 20-25°C in a water bath, and 6N NaOH was added dropwise under stirring to adjust the pH to 3.7, and ceftazidime pentahydrate crystals were gradually precipitated, and then the temperature was adjusted to 0-5°C in an ice-water bath to grow crystals statically. Hour. Then suction filter, first wash with 30ml of water, then with 50ml of acetone, drain, and vacuum-dry to obtain 13.2g of ceftazidime pentahydrate. The molar yield is 81.0%, the content is 99.1wt.%, the polymer is 0.06wt.%, and the weight loss on drying is 13.9wt.%.

Example 8

20 g of unqualified ceftazime pentahydrate of Example 1 was suspended in 120 ml of water, and 99 wt.% acetic acid was added dropwise while stirring until the material was dissolved to obtain a clarified aqueous solution of ceftazime. Then, 22wt.% ammonia water was added dropwise to the obtained solution under stirring condition at a temperature of 30-35° C. to adjust the pH to 1.6, and an off-white precipitate was precipitated, which was filtered off to obtain a filtrate. 22 wt.% ammonia water was added dropwise to the obtained filtrate with stirring to make the pH to 4.7, ceftazidime pentahydrate crystals were precipitated, and then the temperature was adjusted to 0-5° C. in an ice-water bath for 6 hours of static growth. Thereafter, it was filtered by suction, washed with 30 ml of water and then with 50 ml of acetone, drained, and dried in vacuo to obtain 14.2 g of ceftazidime pentahydrate. The molar yield is 78.8%, the content is 98.4wt.%, the polymer is 0.09wt.%, and the loss on drying is 13.7wt.%.

Claims (7)

1. purification process that contains the ceftazime of polymeric impurities, this method comprises:

The ceftazime that will contain polymeric impurities adds in the entry, randomly adds acid and makes its dissolving, obtains the ceftazime aqueous solution; PH with the alkali or the acid adjusting ceftazime aqueous solution is 1.5～2.5 then, has precipitation to separate out; Remove by filter precipitation, it is 3.5～4.8 that resulting filtrate continues to regulate pH with alkali, and controlled temperature is at 0～40 ℃, and the ceftazidime pentahydrate crystal structure is separated out.

2. purification process according to claim 1 is characterized in that, described acid is hydrochloric acid, phosphoric acid, sulfuric acid, formic acid or acetate.

3. purification process according to claim 1 is characterized in that, described alkali is sodium hydroxide solution, potassium hydroxide solution, sodium acetate, Sodium isooctanoate, ammoniacal liquor, triethylamine or n-Butyl Amine 99.

4. according to claim 2 or 3 described purification process, it is characterized in that, removing by filter post precipitation, it is 4.0～4.6 that resulting filtrate is regulated pH with alkali.

5. purification process according to claim 4 is characterized in that, described controlled temperature is 5～30 ℃.

6. purification process according to claim 1 is characterized in that, the described ceftazime aqueous solution, and the concentration of ceftazime is 5wt.%～60wt.%.

7. purification process according to claim 6 is characterized in that, the described ceftazime aqueous solution, and the concentration of ceftazime is 10wt.%～40wt.%.