Method for production of makrolide antibiotic tylosine

FIELD: production of macrolide road-spectrum antibiotic tylosine.

SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.

EFFECT: method for production of tylosine base in granulated form with homogeneous composition.

2 cl, 6 ex

 

The invention relates to the field of biotechnology and concerns a method for obtaining a macrolide antibiotic tylosin, with a broad antibacterial spectrum of activity and low toxicity. Tylosin is used to treat Mycoplasma, dysentery, atrophic rhinitis and other diseases in farm animals and birds.

A method of obtaining tylosin base /Patent US 4568740, C 07 H 17/08 E 33/ - similar, whereby to precipitate tylosin base using an organic solvent, in which tylosin is not soluble, in particular cyclohexane, and carry out deposition by prilipanie cyclohexane to chlorothalidone concentrate tylosin base.

This method has the following disadvantages.

1. When prilivnyi precipitator - cyclohexane to chlorothalidone concentrate tylosin base resinification occurs, resulting in a resinous, fine suspension tylosin, which complicates the process of filtering the obtained resinous, fine mass and drying the finished product.

2. Tylosin base is obtained as an amorphous powder with a particle size of from 20 to 40 μm, interspersed with resin, the content of the active substance is 95%.

By way of prototype /Tadeusz Korzybski, Antibiotics, vol. 1, Warsaw, 1969, s, 58/ organizescooperation concentrate tylosin base while mixing, slowly add hexane to obtain raw tylosin base, which is subjected to a further treatment, which consists in dissolving the obtained drug in acetone and gradually added to the obtained acetone concentrate 10 volumes of water for crystallization tylosin base.

The way the prototype has the following disadvantages.

1. When prilivnyi precipitator - hexane to chloroform concentrate tylosin base resinification occurs, resulting in a resinous, fine suspension tylosin, which complicates the process of filtering the obtained resinous mass and drying of the drug.

2. Tylosin base is obtained as an amorphous powder with splashes of resin.

3. To obtain a homogeneous composition of the drug, without blotches resin, conduct water and the acetone recrystallization, which is associated with additional costs of acetone and its regeneration and leads to additional losses of the target drug. As a result of recrystallization receive product with a particle size of from 30 to 60 μm, the content of the active substance 96%.

The aim of the proposed method is to obtain a preparation in the form of granules, homogeneous composition.

This objective is achieved in that the proposed modified order of mixing the components of the environment of deposition, which consists in prilivnyi organic concentrate tylosin base to asedit the Liu - the hexane with the speed of prilipanie from 3 to 5 ml per minute per 50 ml of an organic concentrate tylosin base.

During prilipanie organic concentrate tylosin base to the precipitator - hexane rapid formation of granules tylosin base, without entrainment of organic solvent (chloroform, butyl acetate, methylene chloride) into granules that can prevent resinification and get the drug in the form of granules, homogeneous composition.

Organic concentrate is a tylosin base in dissolved form in several organic solvents not miscible with water (butyl acetate, chloroform, methylene chloride), with activity from 50,000 to 100,000 IU/ml By the present method organic concentrate tylosin base was prepared as follows.

1. The first extraction from native solution (filtered culture fluid) with an organic solvent (butyl acetate, chloroform, methylene chloride) to obtain the organic extract tylosin base with activity from 10,000 to 20,000 IU/ml

2. The re-extraction solution of tartaric acid with getting tartrate reextract with activity from 20000 to 40000 IU/ml

3. A second extraction with an organic solvent (butyl acetate, chloroform, methylene chloride) obtained from tartaric acid reextract with the teachings of organic concentrate tylosin base with activity from 50,000 to 100,000 IU/ml

You can obtain organic concentrate tylosin base as follows.

1. As described in examples 1 and 4 of the patent US 4568740 using ion-exchange resin and concentration chloridometer extract in vacuum.

2. According to the method of the prototype by concentrating the chloroform extract on a column of activated carbon.

Distinctive features of the proposed method

1. The deposition of tylosin base is carried out by prilipanie organic concentrate tylosin base to the precipitator - hexane.

2. Speed prilipanie organic concentrate tylosin base is 3 to 5 ml per minute per 50 ml of the concentrate.

3. Tylosin base is obtained in the form of granules, homogeneous, ranging in size from 90 to 100 microns.

The inventive method provides

1. Receiving tylosin base in the form of granules, homogeneous, ranging in size from 90 to 100 μm, which provides:

1.1 Satisfactory filterability of the suspension tylosin no “breakthrough” drug through the filter wall due to the absence of fine particles and resin.

1.2 Satisfactory drying process of the drug.

2. Reducing the cost of the drug due to the exclusion of the stage of water-acetone recrystallization.

Examples of the method

Example 1

To 150 ml of hexane at peremeci the years add 50 ml butylacetate concentrate tylosin base with activity 50000 IU/ml at 5 ml per minute. The reaction mixture was kept at a temperature of from 10 to 15°C for 3 hours, after which the precipitate tylosin base is separated by filtration, washed his hexane and dried in vacuum at 40°C for 4 hours. Get 4,75 g tylosin base in the form of a homogeneous granules ranging in size from 90 to 100 μm, the content of the active substance 98%.

Example 2

To 150 ml of hexane was added with stirring 50 ml chloridometer concentrate tylosin base with the activity of 100,000 IU/ml at 5 ml per minute. The reaction mixture was kept at a temperature of from 10 to 15°C for 3 hours, after which the precipitate was separated by filtration, washed his hexane and dried in a vacuum at a temperature of 40°C for 4 hours. Obtain 4.8 g of tylosin base in the form of a homogeneous granules ranging in size from 90 to 100 μm, the content of the basic substance of 98.5%.

Example 3

To 150 ml of hexane was added with stirring 50 ml of chloroform concentrate tylosin base with activity 75000 IU/ml at 5 ml per minute. The reaction mixture was kept at a temperature of from 10 to 15°C for 3 hours, after which the precipitate was separated by filtration, washed his hexane and dried in a vacuum at a temperature of 40°C for 4 hours. Obtain 4.9 g of tylosin base in the form of a homogeneous granules ranging in size from 90 to 100 μm, the content of the active substance 98%.

Example 4

Similar to example 1, but the speed of prilipanie butylacetate concentrate tylosin base is 3 ml per minute.

Example 5

Similar to example 2, but the speed of prilipanie chloridometer concentrate tylosin base is 3 ml per minute.

Example 6

Similar to example 3, but the speed of prilipanie chloroform concentrate tylosin base is 3 ml per minute.

1. The method of obtaining tylosin base, including deposition of tylosin from organic concentrate tylosin base using deposition tylosin base organic solvent is hexane, characterized in that the precipitation is performed by adding organic concentrate tylosin base to the organic solvent is hexane.

2. The method according to claim 1, characterized in that the speed of prilipanie organic concentrate tylosin grounds to hexane is 3 to 5 ml per minute per 50 ml of the concentrate.



 

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