CS239383B1 - The method of isolating pure phenoxymethylpenicillin or benzylpenicillin - Google Patents

Abstract

The purpose of the invention is a method for isolating pure phenoxymethylpenicillin or benzylpenicillin from solutions obtained by extraction of filtered fermentation broth with organic solvents, with effective removal of undesirable ballast substances in the said isolation step. The said purpose is achieved by using for the extraction a mixture of 70 to 99.5 vol. per. butyl acetate and 0.5 to 30 vol. % of an organic solvent miscible or at least partially miscible with water, such as acetone, ethanol, butanol.

Description

239383

The invention relates to a process for the isolation of pure phenoxymethylpenicillin or benzylpentiline. from solutions obtained by extraction of the filtered fermentation broth with organic solvents.

The principle of isolating phenoxymethylpenicillin or benzyipenicline is by filtration of the fermentation broth to remove particulate matter, the filtrate of the fermentation broth is treated by acidification with an organic solvent which is not miscible with water, especially butyl acetate, the penicillin extract is decolorized with an absorbent, the most charcoal and phenoxymethylpenicillin or benzylpenicillin are precipitated 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 the resulting products which must meet different quality requirements.

Patent publications relating to the extraction of penicillins directly from the fermentation broth, the separation of 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 the ballast substances and the solution of the appropriate process for the filtration of the fermentation broth using various inorganic salts and high molecular weight substances are incorporated herein by reference. USSR No. 187 241, US Patent No. 2 471 597, NSR 941 686. However, these procedures only deal with the removal of ballast substances in part.

Many patent publications deal with increasing the extraction efficiency by using suitable extracts (cf. 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] to suitable surfactants (U.S. Pat. No. 2,481,093, U.S. Pat. No. 886,517, U.S. Pat. a suitable pH extraction (U.S. Pat. No. 2,482,938).

Processing of the filtrate extract of the fermentation broth, in most cases of penicillin butylacetate in butyl acetate, includes patent applications according to which the specific properties of phenoxymethyl-penicillin or benzylpenicillin are used, in particular the formation of sparingly soluble salts with alkali. alkaline earth metals, such as sodium, potassium, calcium, salt formation with special organic bases, stability of phenoxymethylpenicillin in acidic solutions.

The essence of the method of isolation according to MS. No. 3,935,335 is the conversion and crystallization of potassium salts by addition of an aqueous solution of potassium acetate to the penicillin extract in an organic solvent. However, the resulting potassium salt is of low quality, therefore it must be recrystallized, washed several times with a suitable organic solvent. resp. in the case of phenoxymethylpenicillin, first prepare the free acid before recrystallization. Thus, the yield of the entire insulation process is considerably 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. No. 127,853. In this process, as well as others (U.S. Pat. No. 2,719,149, U.S. Pat. No. 806,929), the already mentioned purification steps have to be included, thereby reducing the yield of potassium salts to 60-70% by weight based on the starting rich butyl acetate. The shortening, and thus the efficiency of the isolation process, were not made according to other patent documents (French, Pat. No. 1 058 513, Austrian Pat. No. 174,153, U.S. Pat. No. 275,965). of which alkali metal salts of penicillins are used. The above mentioned shortcomings are solved by the procedure of MS. pat. No. 191,597, the addition of water and an organic solvent to the decolorized rich butyl acetate prior to precipitation of potassium salts effectively removes the ballast substances from the previous isolation step. i.e., from the extraction to the starting solid butyl acetate. Českoslov. pat. No. 20,049,09 completes this isolation process to efficiently remove unmetabolized phenoxyacetic acid, if there is an increased content in the fermented base. All previously known methods address the removal of ballast substances that have similar physicochemical properties to acopenicillins, in the phase of the end-processed potassium salts, ie, in the phase-rich butyl acetate-potassium salt, which in some cases, with large amounts of bulk materials. can cause difficulties. This drawback has been avoided by isolating pure phenoxymethylpenicillin or benzylpenicillin from solutions obtained by extraction of the filtered fermentation broth with organic solvents.

The invention is based on the fact that a mixture of 70 to 99.5 vol.% Of butyl acetate and 0.5 to 30 vol.% Of an organic solvent, miscible or at least partially miscible with water, such as acetone, butanol, is used for the extraction. ethanol.

The present invention is based on the understanding that the fermentation broth of both penicillins contains, in addition to the blister materials, organic salts and related physicochemical properties to the penicillin. These are, in particular, p-hydroxyphenoxymethylpenicillin, penicillin K, X, F, dihydro F and their decomposition products.

The inventors have found that these substances in the extraction of the acidic region with a mixture of butyl acetate and organic solvent, miscible or, at least partially, miscible with water, 239383 6

With 2 to 4 times more effective removal than butyl acetate alone. This effect is due to the good solubility of the particulate matter in some aqueous solutions of organic solvents, such as acetone, butanol, ethanol, which ultimately results in an extraction of 2 to 4 times the amount of these substances from the extraction. comes in the waste floor. Thereby, the rich butyl acetate, which is the starting intermediate for further isolation steps, is better, which has a beneficial effect on the efficiency of the further isolation process.

For example, the phenoxymethylpenicillin or benzylpenicillin potassium salt, using the principles of the present invention, can be prepared such that the penicillin extract obtained by extraction of the butyl acetate-acetone mixture becomes 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 dried.

The potassium salt prepared with phenoxymethyl-penicillin or benzylpenicillin with such a salt is of such purity that it meets all the prescribed pharmacopoeial criteria.

According to the process of the present invention, the phenoxymethylpenicillin salt of butbobenzylpenicillin can be produced in an increased yield, while saving raw materials while maintaining the good quality of the resulting products.

EXAMPLES Example 1 To 3,000 ml of an aqueous solution of phenoxymethyl-penicillin at a concentration of 15,200 IU / ml, obtained by filtration of the fermentation vessel and washing the filter cake with water, was 450 ml of butyl acetate and 50 ml of acetone were added and the solution was adjusted to pH 2.9 with 10% sulfuric acid for stirring. The solution was stirred for 15 min, then the aqueous phase was separated from the butyl acetate and the penicillin content determined. In the aqueous phase, 980 IU / mL was determined and 98 500 IU / mL in butyl acetate. 2.0 g of activated carbon was added to the 400 ml butylacetate phase, the suspension was stirred for 45 min. and actively charcoal filtered.

The filter cake was covered with 20 mL of pure butyl acetate. 410 ml of a decolorized extract of 97,400 IU / ml were obtained. 40 ml of water was added to the colored extract and 4 ml of a saturated aqueous solution of potassium acetate were added with stirring. After stirring for 15 min, an additional 32 mL saturated aqueous potassium acetate solution was added and the suspension stirred for 30 min. After separation, the potassium salt was washed with ethanol and acetone and dried. 24.4 g of a white crystalline salt of 1500 IU / mg are obtained, i.e. 80.3%, calculated on the filtrate of the fermentation broth. The absorption ratio of Alfis / Al 2 O was 1.21. Example 2

The same procedure as in Example 1, except that phenoxymethylpenicillin from the fermentation broth filtrate was extracted with 450 ml of butyl acetate and 50 ml of butanol. 24.8 g of white crystalline salt of 1490 ml / mg, ie 81.0 °, were obtained. o, the filtrate of the fermentation tray is counted. A2 absorbance ratio (18 / A274 was 1.22. Example 3

The same procedure as in Example 1, with the exception that phenoxymethylpenicillin from the fermentation broth filtrate was extracted with 450 ml of butyl acetate and 50 ml of ethanol. 23.9 g of a white crystalline salt of 1500 IU / mg, ie 78.6, were obtained. %, calculated filtrate of fermentation broth. The absorbance ratio Α268 / Α274 was 1.21. Example 4

The procedure was the same as in Example 1, except that an aqueous solution of benzylpenicillin at a concentration of 15 600 IU / ml was obtained for the treatment by filtration of the fermentation batch and washing of the filter cake with water. 23.7 g of a white crystalline salt of 1550 IU / mg, i.e. 78.5%, calculated as the filtrate of the fermentation broth. Example 5

The same procedure as in Example 1, except that an aqueous solution of benzylpenicillin at a concentration of 15 600 IU / ml was taken up and benzylpenicillin was extracted with 450 ml of butyl acetate and 50 ml of butanol. 24.2 g of a white crystalline salt of 1 560 IU / mg, i.e. 80.7%, calculated on the filtrate of the fermentation broth, are obtained. Example 6

The same procedure as in Example 1, except that an aqueous solution of benzylpenicillin at a concentration of 15 600 IU / ml was taken up and 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, i.e. 80.3%, are obtained, calculated on the filtrate of the fermentation broth.

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