DD160593A3 - PROCESS FOR REPRESENTING DIGOXIN FROM DIGITALIS LANATA EXTRACTS - Google Patents

Abstract

The invention relates to the field of cardioactive drugs. The aim of the invention is to obtain with few, technologically-technologically simple steps economically in high yield from the raw material Digitalis lanata plant pure digoxin in pharmacopoeia quality. It was the task of making the process largely continuous. This was solved by treating the chloroform extracts obtained after the extraction of the drug with an intermediate cleaning with miramide, after addition of suitable polar solvents, with aqueous sodium hydroxide solution and thus extracting large quantities of dietary fiber and subsequently concentrating extracts of a continuous countercurrent distribution in one The polar phase is concentrated and recrystallized the resulting pure digoxin from a specific solvent. The invention is specifically applicable to the removal of polar, acidic concomitants in cardiac glycosides, especially digitoxin and digoxin, and their purification.

Description

Process for the purification of digoxin from Digitalis lanata extracts

Field of application of the invention

The present invention relates to a process for the purification of digoxin for therapeutic purposes from extracts of Digitalis lanata with high yield and simplified procedure «

Characteristic of the known technical solutions

It is known that in the extraction of digitalis lanata drug to obtain the cardiac active steroid glycosides such as lanatoside A and C or digitoxin and digoxin, with various solvents such as water, alcohols, acetone, ethyl acetate and their Geinischen to varying degrees in addition to the desired compounds a significant proportion of dietary fiber such as chlorophyll, plant acids, phenolic compounds, various steroid glycosides and sapogenins, ait be extracted and the further work-up to the desired products, such as z-B, digoxin, significantly disturb *

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To remove these by-products extraction, distribution, adsorption and crystallization methods have been used, of which several must always be combined to achieve the necessary purification of the desired compounds, such as digoxin and digitoxin *

For the removal of impurities by formation of insoluble salts and simultaneous adsorptive binding treatment with lead hydroxide (DT-AS 1 143 301, CH-PS 176 829), iron hydroxide (DR 707703) or lead acetate (eg Acta Pol. Pharm. XXI 257-63 (1964), however, significant losses occur through equilateral adsorptive binding of the active ingredients, apart from the more difficult technical handling of voluminous precipitates.

Furthermore, it is known from HU-PS 156 753 that one carries out the extraction of Digitalis lanata drug with organic solvents, preferably ethyl acetate, in annnoniakalisehern medium having a pH of 8-12, preferably 8-9, with simultaneous addition of reducing agents and thus reduces the amount of fiber in the further processing stages.

According to DI-PS 41 820, a significant cleaning effect of the. Essigester extracts of Digitalis ianata drug achieved by drying on polyamide powder and selective extraction of glycosides with aqueous alcohols or acetone, but still a considerable part, especially phenolic impurities, not removed *

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The further work-up of the glyeoside extracts pre-purified by one of these methods is carried out by means of multiple decomposition and finally by separation of the more or less pure crystallized glycoside mixture by column chromatography (Austral Journ Pharmacy 36, 1137 (1955) and / or fractionated Crystallization (HU-PS 151 897 and 162 304) or countercurrent distribution (DL-PS 42 345) and the Sinze! Components. The crude glycosides obtained by these methods, such as digitosin and digosin, then have to be recrystallised, often several times, to achieve the required pharmacopoeia quality become.

Thus, according to DT-AS 1 183 627, a distribution of the concentrated crude extracts of the glycosides between water / butanoi / benzene and subsequent transfer into an aqueous methanol solution is proposed treatment with heavy metal salts. The crystallization of the crude glycosides obtained with chloroform from the aqueous methanolic solutions carried out a separation and purification on aluminum chloride columns and then, by crystallization, recovered the pure glycosides digitosine and digoxin. "

These procedures have the distinct disadvantage that the numerous operations, in particular the crystallization of Rohgiycosidgemisches, leads to high losses in the remaining mother liquors, which must be fed to a separate workup that large Lösungsaitteloiengen are needed and a continuous procedure is difficult or impossible .

Siel the invention

The aim of the invention was to reduce the number of lossy intermediates in the purification of Glycoaidkonzentrate, consisting of fiber of various kinds and. the important cardioactive steroid glycosides digitoxin and digoxin, until the recovery of pure heraglycosides, in particular

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of digoxin, to reduce and simplify it and to obtain digoxin of pharmacopoeia quality as low as possible

Explanation of the essence of the invention

Starting from: the intermediate product prepared according to DL-PS 41 820, which is prepared by extraction of the fermented digitalis lanata drug with aqueous ethyl acetate and drying of the concentrated extract on polyamide powder, the glycosides, in particular digitoxin, gitoxin and digoxin, by extraction with aqueous methanol, ethanol, isopropanol or acetone. This extract still contains considerable amounts of undesirable impurities that significantly interfere with the further processing, in particular crystallization of the glycosides. To remove these substances, the glycoside mixture is converted from the aqueous-alcoholic solutions by means of chloroform by stirring or countercurrent extraction into the chloroform phase, wherein the predominant portion of the accompanying substances is extracted with «

The subsequent stage of the crystallization of the glycosides from the distillation residue is tedious and very lossy. According to the invention, this stage of crystallization, if necessary combined with a chromatographic purification, can be avoided if the chloroform solution is diluted with a dilute alkali solution containing alkali metal hydroxide before concentration 0.5 to 5 %, d. In this case, large portions of phenolic and other acidic fibers are converted into the aqueous phase as water-soluble alkali metal salts. In this case, in particular in the presence of methanol in the Chloroform phase, by transfer of the methanol into the aqueous phase and, associated therewith, a distribution of the digoxin between the chloroform and

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the aqueous-methanolic phase and the strong alkalinity of the aqueous phase high-iiVerluste (R * to "C _# Elderfield, J. Chein qrg" S ^ 273 (1941);. Lindig, G. and K * Repke, Arch * exp " Path · Phamu 241 "165 (1961).

These losses can be surprisingly reduced to less than 5%, if according to the invention a polar solvent such as isopropanol, acetone, ethyl acetate or butyl acetate in a proportion of 10 - 50 % Vol,% (preferably 15-30 vol.%), Based on the chloroform extract This result was not to be expected from the outset, since some of the solvents mentioned pass into the aqueous, alkaline phase. However, this does not lead to simultaneous conversion of digoxin into the aqueous phase, since under these conditions, despite the strong polarity of the Digoxin's distribution equilibrium is strongly on the side of the chloroform phase «

The loss of digoxin, in particular by the formation of emulsions, is prevented by adding to the aqueous sodium hydroxide solution a neutral salt, such as sodium sulfate or sodium chloride, in a concentration of 1-5 % . The removal of remaining adhering residues of aqueous sodium hydroxide solution after the alkali treatment is carried out by washing twice with 5% by volume, based on the chloroform extract, of a 1-5% saline solution *

According to the invention, the 'treated with alkali chloroform extracts containing the glycosides Digitoxin and digosin, after concentration without further purification steps, such as. B. crystallization, immediately by Gegenstromverteiiung in the components digitoxin and digoxin separate «

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The separation of the digosin by distribution, in particular continuous countercurrent distribution, is expediently carried out in a solvent system consisting of chloroform, gasoline, methanol and water with a Bm volume ratio of the two phases of 1: 6-7, preferably 1: 6.5 · The feed of glycoside solution can be kept relatively high, zweekmäßigerweise so that a concentration in the Oberphaae (methanol / water) of 2.0 - 3.1 g digosin / 1, preferably 2.8 g digoxin / 1, is reached * Hit this system the glycosides are separated in a continuously working distribution column of a modified Scheibel type, whereby a theoretical number of stages of only 5 is required *

From the aqueous-methanolic upper phase is removed by concentration to 0.2 VT to 0.3 VT, preferably 0.25 VT, the digosin crystalline with a yield of 90 - 95 % and a content of 80 - 90% excreted · This procedure leads Surprisingly, an almost complete separation of the relative to its physical behavior, especially almost the same polarity, the digorsin very similar digosigeninbisdigitoxoside. This lifting glycoside, sometimes up to 20 %, based on digoxin, contained in the dispersed solution can adversely affect the quality of the digosin and often needs to be removed by lengthy cleaning operations *

The crude digoxin is prepared by dissolving in a mixture of methylene chloride / methanol or methylene chloride / ethanol in a volume ratio of 5: 1 to 1: 5, preferably 1: 1, and removing coloring impurities as needed. with 20 to 50 weight percent, based on the raw digosine used, a mixture of activated carbon / alumina in the ratio 1: 1 treated, the solution was filtered clear and concentrated until complete removal of the methylene chloride.

The digoxin crystallizes with a purity of over 96% and a yield of 85-95%. The quality of the digoxin meets the requirements of the internationally important pharmacopoeias.

The invention is explained in more detail by the following examples:

example 1

2 t Digitalis lanata drug with a content of digoxin of 0.20 % and Digitoxin of 0.08% are extracted with the 6-fold amount of aqueous ethyl acetate according to the countercurrent principle (extraction effect about 95 %) and the concentrated extract to 100 kg Polyamide powder (Miramid YS) dried up. This product, about 200 kg, is extracted three times with 600 l of 50% strength methanol according to DL-PS 41 820.

The extracts obtained, about 1,700 l, are extracted three times with a total of 300 l of chloroform, and 60 l of acetone are added to the resulting chloroform extract.

The mixture thus obtained is washed twice with in each case 180 l of a 2% strength aqueous sodium hydroxide solution which still contains 2 % of common salt, for 10 min. stirred, allowed to settle and the aqueous-alkaline solution separated. By washing twice with 2% aqueous sodium chloride solution, the chloroform extract is freed from excess liaOH.

The chloroform solution is then concentrated in weak vacuum at 40 - 50 ⁰ C to about 10 1 and dissolved with a mixture of methanol / chloroform 1: 1 to about 30 1. This solution is used directly in the countercurrent distribution.

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In a continuously operating modified Scheibel column with a theoretical number of stages of 5 in the middle of the column, the concentrated glycoside solution at a rate of 100 g digosin / hour to 36 1 Oberphaae and 5.5 1 subphase fed, as a phase system is chloroform / gasoline / methanol / Water with a composition of the upper phase of 53% water, 42 % methanol and 5 % chloroform and the lower phase of 0.2 % water, 4% methanol, 82 % chloroform and 13.8 % gasoline (by weight) and a volume ratio. the phases of 1: 6.5 (lower phase: upper phase) are used ·

The effluent upper phase (methanol / water), a total of 1200 1, are concentrated to 300 1 at 50 ⁰ C and 50 - 100 Torr and the precipitated digosin is filtered off with suction and dried. Yield: 3 x 200 g digoxin (8 · ssig) ·

The digoxin is dissolved in 35 l of a mixture of methylene chloride / methanol 1: 1 and treated with 0.5 kg of alumina (neutral) and activated charcoal, stirred for 15 min and then filtered. The charcoal / Aluminiumosid residue is washed with 5 1 of the mixture methylene chloride / methanol and the combined solutions at 20 ⁰ C and 100 Torr to 5 - 6 1 concentrated * The precipitated digozin is filtered off with suction and washed with methanol

 Yield after drying: 2.0 kg digosin

with a content of 98 %

(about 50 % d, Th.)

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Example 2

1 t of dried Digitalis lanata drug containing 0.28% digoxin and 0.1% digitoxin is extracted according to Example 1. The extract is concentrated in vacuo and mixed with 60 kg of polyamide powder and dried in a fluidized bed dryer.

The obtained 100 kg of concentrate are three times each. Extracts 250 1 50% methanol and extracted the resulting ca.- 700 1 four times with 50 1 of chloroform. The resulting 200 1 chloroform extract containing 15% methanol are mixed with 60 1 acetone and this solution with 20 1 3% aqueous sodium hydroxide solution containing dissolved 5 % saline, stirred from and then the chloro formicating twice with each washed 20 1 Seiger aqueous sodium chloride solution neutral. This treatment can be carried out by stirring or by means of separators. The cleanly separated chloroform solution, which must be neutral, is concentrated to the viscosity and then diluted 1: 1 with 20 l of methanol / chloroform. The obtained 23 1 solution contain, according to analytical examination, 2,100 g of digoxin.

This solution: is fed in a solvent mixture., According to Example 1 at a rate of 1 1 solution per hour in a Scheibel column with a throughput of 36 1 upper phase and 5.5 1 lower phase per hour. The obtained 2400 1 upper phase are to 25 7ol «%, d. H. BOO 1, concentrated and vacuumed after standing for 10 hours, the precipitated digoxin.

Yield: 2.050 g digoxin with a content of 85% "The digoxin is recrystallized analogously to Example 1. 1,540 g of digoxin with a content of 96 % (55 % of theory ) are obtained,

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Example 3 .

10 kg fermented, dried Digitalis lanata drug with a digoxin content of 0.31%, is added with stirring for 30 min. extracted with 30 1 ethyl acetate with the addition of 3 1 of water · The combined extracts are concentrated at 40 C in vacuo at 100 Torr and mixed with 1 kg of polyamide powder (Miramid FP) and dried at 50 C.

The resulting concentrate of about 2 kg is extracted three times with 5 1 each of a mixture of the same parts of methanol and water and the solution obtained vieriaal with each. Stirred 1 1 chloroform.

The combined chloroform solutions are mixed with 1.5 1 of ethyl acetate and twice 5 min. with 2.5 1 1% sodium hydroxide solution to which 3% sodium chloride was added, stirred. After separation of the sodium hydroxide solution, the chloroform solution is washed neutral with 200 ml of a 3% aqueous Kochaalzlösung twice and concentrated to dryness. The residue is taken up in 250 ml of a mixture of chloroform / methanol 1: 1 and distributed in a laboratory Scheibel column with a theoretical number of stages of 5 in the phase system mentioned in Example 1. The feed of the glycoside solution is carried out in the middle of the column at the rate that the concentration of digoxin in the upper phase, -2. 8 g / l.

The resulting upper phase of a total of 25 1 is concentrated at 50 C and 50 Torr to 6.2 1 and after cooling the solution to 20 ⁰ C, the precipitated Rohdigoxin filtered off with suction and dried at 50 ⁰ C.

The crude digoxin is recrystallized according to Example 1. There are obtained 20 g of digoxin with a content of 97%. The quality corresponds to the A3 2-DDR and USP ΣΙΖ _Ο The yield is 64.5% d Th ₀

Claims (4)

Erfindung3anapruch "Procedure for the purification of digoxin from ethyl acetate extracts of Bigitalia lanata drug which have been pre-purified by drying on polyamide and extraction with aqueous alcohol, characterized in that extracting the aqueous-alcoholic extracts with chloroform, the chloroform extracts after addition of polar solvents such as acetone, ethyl acetate, Iaopro panol or Butylazetet treated with aqueous sodium hydroxide solution, these extracts concentrated and immediately subjected to a countercurrent distribution in a system consisting of Waaaer / methanol / chloroform / gasoline, the polar upper phase concentrated and daa precipitated digoxin processed by a single recrystallization to pure digoxin 2 » method according to item 1, characterized in that one added the polar solvent mentioned in point 1 in an amount of 10-50 Yo1%, preferably 30 Yo1%, based on the chloroform solution 3. The method according to item 1, characterized in that one the aqueous sodium hydroxide solution in a concentration of 0.5'- 5 %, preferably 2 %, used for cleaning. 4. The method according to item 1, characterized in that one uses as a distribution system for the countercurrent distribution, a solvent system Methanel / water / chloroform / gasoline of the following composition: Water methanol chloroform gasoline Upper phase 53 42 5 - Lower phase 0.2 4 82 13.3 (in% by weight) zu'j 3 4 e - ^λ% - Process according to item 1, characterized in that the upper phase of the distribution (aqueous-methanolic phase) is restricted to .20 - 30 %, preferably 25%, of the initial volume. A process as claimed in item 1, wherein a mixture of methylene chloride / methanol or methylene chloride / ethanol in a volume ratio of 1: 5 to 5: 1, preferably 1: 1, is used to recrystallize the digoxin, and a mixture is used to remove coloring matter of alumina and activated carbon in a ratio of 1: 1, in the ratio of 20 - 50 weight percent, based on the digozin used, and after filtration of the solution this bis'- to the complete removal of methylene chloride to about 20 % by volume of the starting solution at 20 C concentrated in vacuo at 50 Torr and the crystallized digoxin filtered off, washed with methanol or ethanol and dried at 50 ⁰ C to constant weight.