CS239383B1 - Isolation of pere phenoxymethylpeniciline or benzyl peniciline - Google Patents

Abstract

The purpose of the invention is to provide a method of isolating pure phenoxymethylpenicillin or benzylpenicillin from the extractions obtained filtered organic fermentation broth solvent, with efficient removal of unwanted ballast substances in said isolation step. This purpose is achieved by taking uses 70 to 99.5 vol. pen. butyl acetate and 0.5 to 30 vol. % organic solvent miscible or at least partially miscible with the incoming, as are acetone, ethanol, butanol.

Description

The invention relates to a process for the isolation of pure phenoxymethylpenicillin or benzylpenicillin from solutions obtained by extracting the filtered fermentation hell with organic solvents.

The isolation of phenoxymethylpenicillin or benzyipenicillin is based on the filtration of the fermentation broth to remove solid particles, the filtrate of the fermentation broth is treated by acid extraction with an organic solvent which is not miscible with water, in particular butyl acetate, the penicillin extract is decolorized with absorbing agent. or benzylpenicillin precipitates in the form of alkali metal salts which are poorly soluble in the organic solvent. The precipitated salts are further processed by various purification operations to produce final products which have to meet different quality requirements.

The patents relating to the extraction of penicillins directly from the fermentation broth without separation of the solid particles have the disadvantage that the extraction efficiency is very low, associated with expensive machinery and equipment (U.S. Pat. No. 2,758,783).

The removal of ballast substances and the solution of a suitable method of filtering the fermentation broth using various inorganic salts and high molecular weight substances are discussed in U.S. Pat. USSR file no. 187,241, amer. no. No. 2,471,597; However, these processes only partially address the removal of ballast substances.

Many patents are concerned with increasing the efficiency of extraction by using suitable extracts (U.S. Pat. No. 2,509,010), suitable organic solvents (French Pat. No. 1038,127, English Pat. No. 760,351, U.S. Pat. No. 2,488,878] with suitable surfactants (U.S. Pat. No. 2,481,098, U.S. Pat. No. 886,517, and U.S. Pat. No. 598,597) and suitable pH extraction. (U.S. Pat. No. 2,482,938).

The processing of the extract of the fermentation broth filtrate, which in most cases is a solution of penicillin in butyl acetate, is dealt with in patents which exploit the specific properties of phenoxymethylpenicillin or benzyipenicillin, mainly the formation of sparingly soluble salts with alkali metals and alkaline earth metals such as sodium, potassium , calcium, salt formation with special organic bases, stability of phenoxymethylpenicillin in acidic solutions.

The essence of the isolation according to MS. pat. file no. 90,335 is the conversion and crystallization of potassium salts by the addition of an aqueous solution of potassium acetate to the extract of penicillin in an organic solvent. However, the potassium salt obtained is of poor quality and must therefore be recrystallized several times with a suitable organic solvent.

respectively. in the case of phenoxymethylpenicillin, prior to recrystallization, the preparation of the free acid should be started first. As a result, the yield of the entire insulation process is greatly reduced. Removal of ballast substances by precipitation of potassium salts from so-called. rich butyl acetate with ethanolic potassium acetate solution and washing with polar organic solvent solves MS. pat. file no. 127 853. In this procedure as well as others (U.S. Pat. No. 2,719,149, English Pat. No. 806,929), the other purification steps mentioned above must be included, thereby reducing the yield of potassium salts to the 60-70% by weight calculated on the starting rich butyl acetate. According to other patents (French, U.S. Pat. No. 1,058,513, Austrian, U.S. Pat. No. 174,153, Swiss Pat. No. 275,965), the isolation procedure has not been shortened and thus made more efficient. formation of alkali metal salts of penicillins. Considerably the above-mentioned shortcomings are solved by the procedure of the MS. pat. file no. 191 597, according to which the addition of water and an organic solvent to the bleached rich butyl acetate prior to the precipitation of the potassium salts effectively removes the ballasts passing from the previous isolation step t. ]. from the extraction to the rich butylacetate starting material. Českoslov. pat. file no. No. 208,049, this isolation procedure will supplement the effective removal of unmetabolized phenoxyacetic acid, if there is increased content in the fermented pod.

All prior art processes address the removal of ballasts having similar physicochemical properties as penicillins in the final potassium salt treatment stage, i. j. in the butylacetate-potassium phase-rich phase, which in some cases, due to the great dispersion of the amount of ballasts, can cause difficulties. This drawback has been eliminated by the isolation of pure phenoxymethylpenicillin or benzyipenicillin from solutions obtained by extraction of the filtered fermentation broth with organic solvents.

The principle of the invention is that a mixture of 70 to 99.5 vol. % Butyl acetate and 0.5 to 30 vol. % organic solvent, miscible or at least partially miscible with water, such as acetone, butanol, ethanol.

The process according to the invention is based on the finding that the fermentation broth of both penicillins contains, in addition to protein ballasts and organic salts, also substances with related physicochemical properties to the penicillins. They are mainly p-hydroxyphenoxymethylpenicillin, penicillin Κ, X, F, dihydro F and their decomposition products.

The authors have found that these substances are removed up to 4 times more efficiently when extracted in the acidic region with a mixture of butyl acetate and an organic solvent, miscible or at least partially miscible with water, than with extraction with butyl acetate alone. This effect is due to the good solubility of the volatile substances in some aqueous organic solvent solutions, such as acetone, butanol, ethanol, which ultimately causes the extraction of 2 to 4 times the amount of these substances in the waste bed. This is rich in butyl acetate, which is the starting intermediate for further isolation steps of better quality, which favorably affects the efficiency of the further isolation process.

Phrasexymethylpenicillin or benzylpenicillin drasein salt, using the principle of the present invention, can be prepared, for example, by extracting the penicillin extract obtained by extraction of the butyl acetate-acetone mixture with decolorizing charcoal, the potassium salt is precipitated with a saturated aqueous solution of potassium acetate in the presence of water, washed with ethanol and acetone and higher.

The potassium salt prepared with phenoxymethylpenicillin or benzylpenicillin in this manner is of such purity that it meets all prescribed pharmacopoeial criteria.

In accordance with the process of the present invention, it is possible to produce a pure drapeable salt of phenoxymethylpenicillin or benzylpenicillin in increased yield, while saving raw material costs while maintaining good quality of the resulting products.

The following examples illustrate the present invention, but do not limit it in any way. Examples of design

Example 1

To 3000 ml of a 15,200 IU / ml aqueous solution of phenoxymethylpenicillin, obtained by filtering the fermentation pod and washing the filter cup with water, 450 ml of butyl acetate and 50 ml of acetone were added and the solution was treated with 10 vol. % sulfuric acid to pH 2.9. The solution was stirred for 15 min, then the aqueous phase was separated from butyl acetate and the penicillin content determined. 980 IU / ml was determined in the aqueous phase and 98,500 IU / ml in the butyl acetate phase. To the 400 ml butyl acetate phase was added 2.0 grams of activated carbon, and the suspension was stirred for 45 min. and activated charcoal filtered.

The filter cake was covered with 20 ml of pure butyl acetate. The obtained 410 ml of decolourised extract at a concentration of 97 400 IU / ml. To the decolorized extract was added 40 mL of water and 4 mL of saturated aqueous potassium acetate solution with stirring. After stirring for 15 min, an additional 32 mL of saturated aqueous potassium acetate was added and the suspension was stirred for 30 min. After separation, the potassium salt was washed with ethanol and acetene and dried.

The obtained 24.4 g of white crystalline salt with an efficiency of 1500 IU / mg, i.e. 80.3%, calculated on the fermentation pod filtrate. The absorbance ratio of A-1A ₂₇₁ was 1.21.

Example 2

The procedure was the same as in Example 1, except that phenoxymethylpenicillin from the fermentation pod filtrate was extracted with 450 ml of butyiacetate and 50 ml of butanol. 24.8 g of a white crystalline salt of 1490 mi / mg, m.p. j. 81.0%, calculated on the fermentation tray filtrate. The absorbance ratio Αυ ^ / Α · · was 1.22.

Example 3

The procedure was the same as in Example 1, except that the phenoxymethylpenicillin from the filtrate of the fermentation pod was extracted with 450 ml of butyl acetate and 50 ml of ethanol. 23.9 g of a white crystalline salt with an efficiency of 1500 IU / mg, m.p. j. 78.6% calculated on the fermentation tray filtrate. The absorbance ratio was 1.21.

Example 4

The procedure was the same as in Example 1, except that an aqueous solution of 15,600 IU / ml of benzylpenicillin was obtained by filtration of the fermentation broth and washing the filter cake with water.

23.7 g of a white crystalline salt of 1550 IU / mg, m.p. j. 78.5% calculated on the fermentation tray filtrate.

Example 5

The procedure was the same as in Example 1, except that an aqueous solution of 15,600 IU / ml of benzylpenicillin was taken for treatment, and the benzylpenicillin was extracted with 450 ml of butyiacetate and 50 ml of butanol.

24.2 g of a white crystalline salt of 1560 IU / mg, m.p. j. 80.7% calculated on the fermentation tray filtrate.

Example 6

The procedure was the same as in Example 1 except that an aqueous solution of 15,600 IU / ml of benzylpenicillin was taken for treatment and the benzylpenicillin was extracted with 450 ml of butyl acetate and 50 ml of ethanol.

24.1 g of a white crystalline salt of 1560 IU / mg t is obtained. j. 80.3%, calculated on the fermentation tray filtrate.

Claims (4)

SUBJECT A process for the isolation of pure phenoxymethylpenicillin or benzylpenicillin from solutions obtained by extraction of a filtered fermentation broth with organic solvents, characterized in that a mixture of 70 to 99.5 vol. % butyl acetate and 0.5 to 30 vol. % organic solvent miscible or at least partially miscible with water such as acetone, butanol, ethanol. 2. The method of isolation according to claim 1, characterized in that a mixture of 95 vol. % butyl acetate and 5 vol. % acetone. 3. The method according to claim 1, wherein a 95 vol. % butyl acetate and 5 vol. % butanol. 4. The method according to claim 1, wherein a 95 vol. % butyl acetate and 5 vol. % ethanol. Severography, n. p., plant 7, Most c «to 2.40 Kčs