DD298997A7 - PROCESS FOR CLEANING RAW DIGOXIN - Google Patents

Abstract

The invention relates to a process for the purification of crude digoxin. The aim of the invention was to convert the crude digoxin obtained after the separation of the main glycosides digitoxin and digoxin in a technically simple operation and with high yield into at least 96%, practically foreign glycoside-free digoxin. This goal is achieved by dissolving crude digoxin with a minimum content of 60% in a mixture of methylene chloride and ethanol in the ratio of preferably 1: 2, then adding about 2 times the amount of water, stirring and filtering off the precipitated digoxin. According to a variant of the invention, 10-20% of an activated carbon / alumina mixture (mixing ratio preferably 1: 1) are stirred into the methylene chloride / ethanol solution of the glycoside to remove the dyeing constituents and subsequently filtered off.

Description

Field of application of the invention

The process for the preparation of pure digoxin finds in the pharmaceutical industry in the isolation of the pure glycoside digoxin from Digitalis lanata drug application. The pure digoxin produced thereafter is used for the treatment of heart disease, especially heart failure.

Characteristic of the known technical solution

To obtain the digoxin from plant material of Digitalis lanata, a number of methods are known, starting from drugs with a digoxin content of 0.1-0.6% digoxin by extraction and removal of a large portion of the ballast; (as flavones, tannins, sugars, dyes, etc., by precipitation or extraction procedures give an enriched glycoside mixture containing mainly digitoxin and digoxin, which can be separated by distribution methods.) However, these glycosides, which are important for therapy, are always accompanied by by-glycosides, which are difficult or impossible to separate owing to very similar physical properties by simple distribution processes, such as continuous countercurrent distribution or even crystallization, It is known that such glycosides, such as, for example, gitoxin, gitoxigenin bis- and monodigitoxoside, diginatin, neodigoxin, digoxigenin bis- and monodigitoxoside can be separated by column chromatography or by Craig distribution in a suitable solvent system.

Thus, digoxin recovered by partitioning is purified by filtration through an alumina column and repeated fractional crystallization from chloroform / benzene, but nothing more is said about the losses and purity. (Chim.farm.Jorunal 7 [1973] 9, p.33, Makarevic et al.)

According to DE-AS 1183627, the crude digoxin is separated by column chromatography on alumina in chloroform-benzene, with details of the purity are not made.

In HU-PS 164706, the crude glycosides, in particular digoxin, which was obtained by distribution and fractional crystallization from octane-dimethylformamide-ethanol-chloroform, are then purified by means of multiple recrystallization from dioxane-ethanol-heptane. About the obtained purity and the Nebenglykoside nothing more is stated, but related only to the content of Gitoxin and Digitoxin.

In HU-PS 151897 digoxin is purified from gitoxin by fractional crystallization from chlorinated hydrocarbons and lower aliphatic alcohols followed by column chromatography on silica gel / formamide with mixtures of aromatic hydrocarbons and ketones. In particular FaI! is used for the fractional crystallization methylene chloride / methanol 1: 1 and for the chromatography benzene / acetone.

The cited ancestors for the production of pure digoxin require a considerable amount of sometimes expensive solvents, or a lot of work. The multi-stage discontinuous operation, such. As fractional crystallization or by Säuhnchromatographie, which requires ongoing monitoring, also proves to be a disadvantage.

Zi \ ii of the invention

D. The object of the present invention was to obtain the crude digoxin obtained from the working up after the separation of the two main glycosides digitoxir and digoxin by continuous countercurrent distribution, which has a digoxin content of 60-90%, by a technically simple procedure To convert a pure digoxin of internationally required pharmacopoeial quality of at least 96% digoxin, the yields should be more than 80% if possible.

-2- 298 997 Dailsetzung the nature of the invention

The crude glycoside mixture of the secondary glycosides arising from the digitalis lanata drug through various extraction and work-up steps mainly consists of digitoxin, gitoxin and, above all, digoxin. The whitening of this mixture takes place predominantly by utilizing the different polarity of the glycosides, often combined with the solubility in various solvents.

A proven method for separating the components is the continuous countercurrent distribution. The thereby obtained from the polar, usually aqueous-alcoholic phase, digoxin always contains varying amounts of Begleitglykosiden similar polarity, especially Gitoxin, Gitoxigeninmono- and bisdigitoxoside, diginatin, neodigoxin and digoxigenin bis- and monodigitoxoside. These accompanying glycosides are difficult to remove, such as multiple crystallization (fractionation) or elaborate distribution methods, such as column chromatography.

The main impurities are diginatin and digoxigenin bisdigitoxoside, which often make up more than 10% of the total. It has now been found that these compounds can be surprisingly easily and almost completely removed by crystallization from a mixture of methylene chloride-ethanol-water. Dyeing fractions can be easily removed by treating this solution with a mixture of activated carbon / alumina.

According to the invention then the digoxin separated by known methods, in particular by countercurrent distribution of digitoxin, which has a content of 60-90% of digoxin and in addition to coloring impurities mainly Gitoxin, diginatin and Digoxigeninbisdigitoxosid and a number of other by-products in an amount of less 1%, in the 20 to 40 times volume (based on the weight of the amount of crude digoxin used). % by volume of a mixture of methylene chloride / ethanol in a volume ratio of 1: 5 to 3: 1, preferably 1: 2, to remove coloring matters, a mixture of alumina / activated carbon in a ratio of 2: 1 to 1: 3, preferably 1: 1, in an amount of 0.1-0.5 parts by weight, based on the crude digoxin added, stirred for 15-30 minutes, filtered off the alumina / charcoal mixture and the clear, possibly slightly colored solution, with the 1.5 - Up to 5fachbn, preferably 2 times the volume length of distilled water and stirred for 1 hour. After standing the solution for 2-20 hours, the precipitated digoxin is filtered off, washed with pure methylene chloride and water and dried. The substance contains more than 95% digoxin and secondary glycosides only a maximum of 2% diginatin and a maximum of 3% digoxigenin bisdigitoxoside. The glycoside thus obtained corresponds in terms of color, optical rotation, content of digoxin all the requirements of international pharmacopoeias.

example 1

100 g digoxin containing 87% digoxin, 3% diginatin, 2% gitoxin and 7% digoxigenin bisdigitoxoside are dissolved in 11 methylene chloride and 21 ethanol with stirring and filtered off from any mechanical impurities present.

To the clear, colorless solution is added 6 l of distilled water with vigorous stirring and stirred for 1 hour. The solution is allowed to stand for a further 3 hours and the precipitated digoxin is filtered off. The white, finely crystalline digoxin is dried at 50 ° C in a vacuum oven.

Yield: 85g pure digoxin-95% of theory

The analytical examination revealed

Digoxin 98%

Diginatin 1%

Digoxigenin bisdigitoxoside 2%

no other glycosides

optical rotation: 13.9 ° (pyridine) according to (USP XIX)

Dry loss: 0.1%

Example 2

0.5 kg of crude digoxin with a digoxin content of 75%, 3% diginatin, 2% Gitoxin, 1% Digitoxin and 9% Digoxigeninbisdigitoxosid is dissolved in 51 methylene chloride and 81 ethanol and treated with 50g activated carbon and 50g alumina (neutral) and stirred for 15 minutes , The solution is then filtered and the clear, almost colorless solution is mixed with 50 ml of distilled water and stirred for 1 hour.

The solution is then allowed to stand for 2-3 hours and sucks the precipitated digoxin. The substance is then dried in vacuo at 50- 0 ° C.

Yield: 350g digoxin = 90% of theory

The analytical examination revealed

97% digoxin

<2% diginatin

<2% digoxigenin bisdigitoxoside no other glycosides detectable optical rotation: 13.8 ° (pyridine) according to (USP XIX) dry loss: 0.25%

Example 3

50 g of crude digoxin with a digoxin content of 70%, 2% Digitoxin, 3% diginatin, 2% Gitoxin and 7% Digoxigeninbisdigitoxosid were dissolved in 550 ml of methylene chloride and 1000 ml of ethanol and mixed with 25 g of activated charcoal and alumina and stirred for 30 minutes. The solution was filtered through a fine filter clear and distilled with 3.51. Water added with stirring. Crystallization started after 5 minutes. After 1 hour, the stirring was stopped and after standing for 3 hours, the precipitated crystals were filtered off with suction, washed with 100 ml of methylene chloride and then 200 ml of water and the substance dried at 60 ° C in a vacuum:

Yield: 32g containing 98% digoxin (89.5%)

Minor glycosides: diginatin; 1 %

Digoxigeninbisdigitoxosid 1% Optical rotation: 13.8 ° (pyridine) 25 ⁰ C loss on drying: 0.13%

Claims (5)

1. A process for purifying crude digoxin by recrystallization and treatment with surface-active adsorbents, characterized in that crude digoxin having a minimum content of 60% in a mixture of methylene chloride and ethanol in the ratio Ί: 5 to 3: 1 dissolves, then with the 1 , 5 to 4 times the amount of water, stirred for at least 2 hours and the precipitated digoxin sucks and dried. 2. The method according to item 1, characterized in that the ratio of methylene chloride to ethanol is preferably 1: 2. 3. The method according to item 1 and 2, characterized in that the methylene chloride-ethanol solution preferably 2 times the amount of water is added. 4. The method according to item 1, characterized in that the removal of coloring constituents additionally the methylene chloride-ethanol solution of glycoside with 10-20% (based on the amount of glycoside used) of an activated carbon / alumina mixture in the ratio 5: 1 to 1 : 5, stirred for 10 minutes and filtered. 5. The method according to item 4, characterized in that the ratio of activated carbon to alumina is preferably 1: 1.