NL8204533A - METHOD FOR WINNING LAXATIVE COMPOUNDS FROM DRIED SENNA. - Google Patents

Description

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Method for recovering laxative compounds from dried senna.

The invention relates to a method of recovering laxative compounds from dried senna.

Dried senna consists of dried leaves and caps ae senna plant, for example the Indian senna (Cassia 5 angustifolia) and the Egyptian senna (Cassia acutifolia). The laxative effect of the dried senna is based on chemical compounds, the sennosides.

The laxatives in dried senna are bimolecular glykoside derivatives of the two anthracene compounds Rhinein aloe modin. The most important are the sennosides A, B, A, |, C and D. Sennosides A, B and A ^ are bisgluko-sylrheine anthrons, sennosides C and D are glykosylrheine-glykosylalemodine anthron compounds.

! In addition to the sennosides, the crude dried product also contains aglucones (sennidines) and other decomposition products and derivatives of the sennosides. These are partially laxative, but can also be toxic and trigger unwanted side effects. Side effects typical of Senna preparations include nausea, vomiting, gas development, chickles and diarrhea.

Several methods for extracting the laxative agents from dried senna have been described. The major laxative-acting glucosides, sennoside A and B, were first recovered from dried senna by Stoll et al., Helvetica Chimica Acta XXXII, Fasciculus VI (1949) 1892. Thereafter, more patents have been disclosed describing processes for preparing sennoside concentrates.

In known prior art processes, the preparation of the senna extract is generally described in 8204533-1. * 3 - 2 - two stages performed.

In the first step, vegetable pigments, fats and other impurities are removed with a suitable solvent, for example with chloroform, ether (US 5 3,089,914) or with 90% methanol (German Aus 1,617,667).

After this preliminary extraction, the active glukosides are extracted in the second stage with methanol, methanol-water, ethanol-water or only with water from the dried product.

To facilitate extraction, the methanol used can be made alkaline by addition of organic base (German Patent 23,397). The organic bases form soluble salts with the sennosides in methanol, which can be easily extracted. A drawback of this method is that the extract has a high impurity content.

It has also been proposed to use extract solvents acidified with citric acid (French patent M6611 (1969)) or with oxalic acid (British patent 832,017). In the latter case, 70% ethanol is used as the solvent. When acidic methanol or an acidic methanol-water mixture is used for the extraction, the impurity content in the extract is less than when the extraction is carried out with basic solvents or with water alone. However, these processes have the drawback that the sennosides, which are acidic compounds, as free acids are only slightly soluble in the solvents used. Therefore, the amount of solvent required for the extraction is very large and may comprise 15 to 30 times the amount by weight of dried product used.

It is also known with phosphoric acid acidified methanol-tetrahydrofuran, methanol-dioxane and tetrahydrofuran-dioxane mixtures (Hungarian patent 6006 (1973)) and water 35 (German Auslegeschrift 1,617,667) as a solvent in the extract 8204533 f ·· \ ï - 3 - use it. These solvents, however, activate the glucosidase enzymes such that some of the active glucosides are hydrolyzed, especially when working in weakly acidic solutions, the pH of which corresponds to that of the original plant material. This leads to a reduction of the active substances in the extract, see also German Offenlegungs-script 2.915.063.

In the prior art processes, the recovery of the sennoside concentrates from the extracts takes place in various ways.

A solid, sennoside-containing concentrate is obtained by careful drying of the extract (German Auslegeschrift 1,617,667). The product then contains all substances present in the extract. The sennoside content of the product is about 17 to 18%.

However, the sennosides can be more selectively separated if they are precipitated from aqueous solutions by the addition of organic solvents. The product obtained contains less bulking agents and has a sennoside content of 60-70%. Precipitation can be carried out by adding diethyl ether (French patent M6611, Magyar G. et al, Hungarian patent 6006 (1973)), isopropyl alcohol after treatment with strongly acidic ion exchange resin (British patent 832,017) or ethanol (Finnish patent 41,588) » Optionally, the sennosides in the solution in the calcium salts (U.S. Pat. No. 3,089,814,

Finnish patent 41,588) are converted and then precipitated by the addition of organic solvents, so that the active glucosides are obtained as calcium salts. The content of sennosides in the precipitated product is then about 60-70%.

To recover pure sennosides as free acids, the sennosides are recovered as calcium salts and these salts are treated with oxalic acid (Stoll et al. Helvetica 35 Chimica Acta XXXII, Fasciculus VI (1949) 1892).

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According to this prior art process, therefore, extracts and various concentrates containing laxative substances can be prepared from dried senna. The amount of laxative active substances in the concentrates depends on the content of these substances in the original dried product and on the method of preparation.

The difficulty in standardizing the senna preparations lies in the determination of the senna glycosides. The dried product contains various compounds, which are included in the determination of the sennaglykosides. However, the physiological action of these individual compounds is not the same. Since it is not possible to distinguish the sennaglykosides from other compounds, which have different physiological actions and possible side effects, by the conventional assay methods, it is difficult to prepare from the conventional senna extracts preparations, which always have the same and reproducible action with the same dose deliver.

The present invention aims to provide a method of recovering laxative compounds from dried senna, which allows the recovery of the laxative substances from dried senna in as concentrated a form as possible and as free as possible from components with undesired side effects in improved yield.

Thus, the invention is characterized in that a. The dried senna is extracted in a countercurrent circulation with a methanol / water mixture and the extract is concentrated at a temperature of 450 ° C until the methanol is completely removed from the extract, b. . cleans the resulting concentrate by continuous liquid-liquid extraction with an organic solvent, c. transfer the obtained raffinate to a crystallizer and acidify it with stirring to a pH of about 1.5-2.0, seed with sennoside crystals, crystallize with stirring and obtain the crystalline crude sennosides obtained 8204533 - 5 - separates and d. the crude sennosides optionally recrystallized.

5 Characteristic data.

Methyl alcohol-water mixtures in which the sennosides are soluble are used to carry out the present process. Preferably 70% methanol is used, since the maximum solubility of the sennosides at methanol concentrations is from 60 to 70%. The extraction is carried out in portions and preferably at slightly elevated temperatures, at most, however, at a solvent temperature of + 35 ° C.

Since there is a danger of the sennosides decomposing, elevated temperatures have previously been avoided. Surprisingly, however, it was found that the sennosides do not decompose at slightly elevated temperatures when using methanol as the solvent.

The extraction of the dried senna is performed in a countercurrent baffle. In general

2 to 4 percolators are used. If the extraction solvent is to be heated, it is also circulated through an external heat exchanger and heated to the desired temperature, however at most 35 ° C. As more percolators are used, the solvent must be heated less. The extract obtained then contains less harmful impurities and the sennosides crystallize out completely from the mother liquor.

For the extraction, the dry charge is preferably swelled in a solvent, preferably using the naper colate of a previously extracted charge.

To this end, the dry charge is introduced into a percolator, covered with a perforated plate weighing about 0.7 kg / dm2 and the solvent or the aftercolate is introduced. The required amount by weight of solvent is about three times the amount by weight of dry charge. Preferably, it is left overnight and the extraction begins the next day.

The extraction takes place in the course of 16-20 hours. During this time, the required amount of 70% methanol is allowed to flow through the batch. Since more percolators are advantageously used, the solvent in the extraction is first passed through the percolator series percolator, which contains the weakest charge, ie the charge already extracted most of the charge and which must be emptied next. From this percolator, the solvent is passed to the next percolator, and so on. The main extract is extracted from the perkolator, which was first filled. In addition, after extraction of the appropriate amount of extract, a further postcolate is recovered in order to swell the new dry charge therein. For this purpose, the perkolator with the weakest charge is emptied, filled with part of the load, the postcolate is introduced and the extraction is carried out the following day.

According to the method of the invention it is possible to extract part of the dry charge with only 4 parts of extraction solvents. When 70% methanol is used at room temperature, the amount of residual in the charge is about 41% per perkolator in the perkolator series. With perkolators the extraction yield (1 -2 25 0.41) x 100 = 83% and with three perkolors connected in series (1 - 0.413) x 100 = 93%.

After the extraction, the methanol is removed almost quantitatively from the percolate, the volume of the bottom product obtained being about 1/5 of the volume of the percolate. The methanol is distilled off to remove it by means of a vacuum distiller equipped with a fractionation column. Due to the risk of hydrolysis for the sennosides, the temperature must not rise above + 50 ° C.

After the methanol has been distilled off, 8204533 1 '- ... ^. ^ · _ -Φ · - - --- - 7 - man cleans the concentrate by liquid-liquid extraction with an organic solvent. As organic solvents, water-soluble alcohols and ketones such as butanol, methyl ethyl ketone and methyl isopropyl ketone can be used. Preferably, butanol-2 is used as the solvent.

The liquid-liquid extraction is carried out as a continuous process in a manifold with a separation action of about ten theoretical steps. The pH of the added concentrate solution is 4.5-5.6, because at this pH the salts of the agluconic compounds present in the dry senna are hydrolyzed to such an extent that the aglucones are removed almost quantitatively from the raffinate.

Preferably, the butanol-2 used in the extraction is saturated before use with water. The supplied concentrate, which is to be extracted, is a highly concentrated solution with a dry matter content of 20-30%.

It contains salts, sugar, amino acids and other water-soluble compounds, which come from the plant mass.

The extraction is preferably carried out such that the run-out ratio of butaol-2: raffinate is 0.7 to 0.8: 1.

The liquid-liquid extraction removes from the solution fats, harmful plant pigments, chlorophylls and carotinoids, free fatty acids, steroids, agluconic anthracene derivatives, neutral glucosides, vegetable waxes and washing alcohols, flavones and other phenols, etc. The raffinate obtained is thereby freed from harmful contaminants so far that most of the senosides crystallize directly from the raffinate phase after acidification with an inorganic acid to pH 1.5-2.0. Hydrochloric or sulfuric acid is preferably used as the anoric acid.

In order to allow the sennosides to crystallize from the raffinate phase, they are placed in a container and, with stirring, so much acid is introduced into the liquid that the pH of the solution becomes 1.5-2.0. The solution is then inoculated with sennoside crystals and left to stir for a week.

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- 8 - crystallize.

On the other hand, the crystallization can also be carried out in a continuously operating crystallizer.

The raffinate phase remains in this crystallizer for a week and is divided between two or more series-connected containers which open into a decanter. The crystallization containers are continuously stirred weakly and inorganic acid is added to the first container to acidify the solution with stirring. The vertical laminar flow in the containers is 0.3-0.4 mm / minute.

This flow rate guarantees satisfactory sedimentation. The crystallized product is filtered off, washed with water and methanol or acetone and then dried. The crude product is optionally recrystallized, as explained below. .

The crude sennosides obtained after crystallization can be recrystallized if desired. Preferably, the crude sennosides are suspended for this purpose up to 10% in an acetone / water mixture (50:50), dissolved by adding NaOH to pH 7.5-9 under sodium salt formation and the sennosides are reprecipitated. adjust the solution to pH 1.5-2 with hydrochloric acid, separate, wash with acetone / water and dry.

With the method of the invention it is therefore possible to recover the sennosides from the raw charge almost 100% pure. Moreover, the process of the invention to recover laxative agents from dried senna no longer requires preliminary extraction of the batch, as is required in the prior art processes.

Since the sennosides obtained according to the process of the invention are chemically and pharmacologically completely characterized, they can be used to prepare drugs with certain galenic properties. In contrast, according to the methods of the prior art, only more or less indefinite galenic extracts can be obtained.

The following examples illustrate the invention. _ - »- ..I, * --------------- -----. 1: ': <-' W '';: .....

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Example I

40 kg of dried senna are placed in two percolators connected in series with a volume of 250 liters and covered with a perforated steel plate.

As extraction solvent, 70% methanol is used, which is fed onto the charge in the first percolator. At the bottom of the perkolator is a bottom plate covered with a filter cloth. The solution is passed onto the charge contained in the second percolator through an emptying valve arranged under this plate. The solvent is thereby allowed to flow freely through the first percolator. The solvent is then passed by means of a siphon from the emptying tap from the first perkolator to the second perkolator. The flow rate of the solution is adjusted with the emptying valve on the first percolator. The outlet of the second percolator is controlled so that the solvent in the second percolator is high enough to cover the perforated steel sheet with a weight of 0.7 kg / dmz.

A total of 160 liters of solvent is used for the extraction of 40 kg of dried senna. After this volume of 70% methanol has been passed through both percolators and the corresponding quantity of percolate has been collected, the emptying hose of the percolator is connected to an after-percolate container and an additional 60 liters of 70% methanol is passed through the percolators. The remaining free solvent is then passed from the first percolator into the upper part of the second percolator and the aftercolate is collected until it totals 120 liters. The first perkolator is then emptied, refilled with 40 kg of dried senna and the naperkolate is pumped onto the load, 120 liters of naperkolate being sufficient to cover the load in the perkolator. A hose connection is then made from the outlet to a pump and a heat exchanger and from there to the lid of the percolator and the solution is circulated until the temperature of the solution is + 30eC. Then it is left overnight.

The next day this percolator is connected to that for extraction and the extraction is carried out as described above.

160 liters of perkolate are collected for each 40 kg load, from which the methanol is removed in a vacuum rotary evaporator equipped with a filling column. Approximately 30 liters of bottoms are obtained, which is extracted in a 10 ', Mixer-Settler "apparatus (10 stages) with 40 liters of butanol-2 saturated with water. 38- 40 liters of aqueous raffinate and 30- 32 liters of butanol-2 extract.

The aqueous raffinate is acidified with 93% sulfuric acid under stirring for 20 hours using 1.6 volume% (based on the volume of liquid to be acidified). The acidified solution then has a pH of 1.5-2.0. Stirring is continued for 6 days, the precipitate is allowed to settle overnight, filtered, washed with water until the wash water is colorless, washed with methanol and dried in an air stream at room temperature. The yield per 40 kg of starting material is 760-790 g (dry matter) with a sennoside content of 90-94%.

The yield therefore constitutes about 70% of the amount of sennoside contained in the starting material.

0.5 kg of crude product is suspended in 5 liters of 1: 1 acetone-water mixture, 48% sodium hydroxide solution is added with stirring until the pH of the solution is 8.5-9, the undissolved residue is filtered off and the filtrate is concentrated. (35%) hydrochloric acid until the pH of the solution is 1.5-2. It is stirred until crystallization begins and then crystallized for at least 3 hours. The precipitate is filtered out of the solution, washed on the filter with 0.5 liters of water and 0.5 liters of acetone and dried in an air stream at room temperature. 1/5 of the mother liquor can be treated with wash water and wax acetone and use this solution as a crystallizing solvent for the next equal portion of the crude product. The yield per 0.5 kg of crude product is 0.460 kg (dry matter) with a sennoside content of 98-99%.

Example II

It works as in Example 1 but uses three series connected percolators and does not heat the 70% methanol. Incidentally, one works as in example I and uses 160 liters of solvent per 40 kg load. 0.890 kg of crude sennoside product with a sennoside content of 92% (dry matter) is obtained per 40 kg load. The crude product can be recrystallized as in Example I.

Example III

Extracted, the methanol was removed. .

It extracts and performs the liquid-liquid extraction as described in Example I. After treatment with butanol-2, the sennoside mixture is allowed to crystallize from the raffinate in a continuously operating crystallizer. For crystallization, two series-connected containers and a third container are used as the canter, which is connected in series with the other. In the last container, the sedimentation of the sennoside mixture is carried out, whereby most of the precipitate is separated from the mother liquor. For this purpose, the raffinate phase obtained after cleaning with butanol-2 is introduced into the first container at a flow rate of about 2 liters / hour. 93% sulfuric acid in an amount of 1.6% by volume of the raffinate is simultaneously pumped into this container. In order to prevent sedimentation at this location, the liquid in the first container is stirred continuously.

The suspension from the first container is then passed over a free overflow in the second container, which is also equipped with a stirrer, and from there over a free overflow into the third container, where the precipitate is allowed to settle, the mother liquor being again through a free overflow in a waste solution container. The precipitate is withdrawn from the third decanter as a thick suspension by means of a bottom-mounted tap 8204533-12, filtered with a suction filter, washed with water and methanol and dried at room temperature in an air stream. The yield per 40 kg of starting material used is 709 g. Seimoside content 91%.

Example IV

The liquid-liquid extraction and recrystallization extraction described below are shown schematically in Figures 10 1-3.

The charge is extracted in a four-stage countercurrent baffle at room temperature. In it, 40 kg of senna caps are placed daily in one of four conical round bottoms and the load is weighted with a plate provided with holes.

Then, in countercurrent, as much 70% methanol is passed through the four-part battery until the fresh cap filling is completely covered with liquid. After at least 12 hours of mashing, perkoling is continued until a total of 160 liters of 70% methanol is passed through. From the container coated with fresh solvent, the extraction liquid is then completely fed into the downstream container and the extraction residue is dried to recover the solvent. The holder is now available to receive the next load of 40 kg and therefore changes at the end of the battery. The extraction yield per percolation step is about 60%. Approximately 120 liters of primary extract are obtained from each 40 kg of senna caps used, which is concentrated to about 30 liters under vacuum in a rotary evaporator with a rectifying attachment. The temperatures may not rise above 50 ° C in the production area.

In order to keep the subsequent liquid-liquid extraction free from interference, the methanol must be completely removed. An attempt is then made to find out whether the concentrate is free from me-35 thanol (GC) and then treated with approximately 2% butanol-2.

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The pH of this extract concentrate is about 5.8.

For the subsequent liquid-liquid extraction, the concentrate is treated in a ten-stage mixer-separator battery (each stage approximately 5 liters) without prior filtration with butanol-2. At an initial ratio of butanol-2: extract concentrate of 1.5: 1, the ratio of butanol-2 extract: extract raffinate is 0.7 to 0.8: 1. Average residence time per staircase approximately 20 minutes.

The extract traffinate 10 obtained is then adjusted to about pH 2 with 94% sulfuric acid and passed into a three-stage crystallizer.

In order to start the crystallization, one is inoculated and then allowed to crystallize at room temperature for about five days. The resulting crystal slurry is extracted from the bottom of the third crystallization container. The extracted crystal slurry is filtered off and the mother liquor is returned to the crystallizer. The crystals are then washed with water, then with methanol and dried in vacuo at 40 ° C. Crude setmoside with a purity of about 90% is obtained. The butanol-2 extract is completely concentrated to recover the butanol-2 and a dark brown to black residue is obtained. The distillate returns to the liquid-liquid extraction.

The crude sennosides obtained are then suspended to about 10% in an acetone-water mixture (50/50) and allowed to dissolve completely by adding sodium hydroxide solution to about µl 7.5 under sodium salt formation. The sennosides are then precipitated by adjusting the hydrochloric acid solution to pH 2, the precipitated product is separated off, washed briefly with acetone water and dried. In this way, based on the senna caps used, about 2% pure sennosides (A and B) are obtained.

35 8204533

Claims (11)

Process for the recovery of laxative compounds from dried senna, characterized in that a. The dried senna is extracted in a countercurrent circulation with a methanol / water mixture and the extract is concentrated at a temperature of ^ 50 ° C until the methanol has been completely removed from the extract, b. cleans the resulting concentrate by continuous liquid-liquid extraction with an organic solvent, 10 c. place the obtained raffinate in a crystallizer and acidify it with stirring to a pH of 1.5-2.0, seed with sennoside crystals, crystallize with stirring and separate the obtained crystalline crude sennosides, d. the crude sennosides, if desired, recrystallize and optionally convert to a pharmaceutically acceptable salt with a pharmaceutically acceptable base. 2. Process according to claim 1, characterized in that as extractant in step a. 70% methanol is used. 3. Process according to claim 1 or 2, characterized in that the extraction of step a. Is carried out at a slightly elevated temperature up to a maximum of 35 ° C. 4. A method according to any one of the preceding claims, characterized in that the senna caps are swelled in a napolate before the percolation. Process according to any one of the preceding claims, characterized in that the concentrate obtained in step a. Is treated with 5% butanol-2. 6. Process according to claim 1, characterized in that the organic solvent used in step b. butanol, 824545 # methyl-ethyl-ketone and methyl isopropyl-ketone. Process according to claim 6, characterized in that water saturated butanol-2 is used. 8. Process according to claim 7, characterized in that the run-out ratio of butanol-2: raffinate is 0.7 to 0.8: 1. Process according to claim 1, characterized in that step c. with hydrochloric or sulfuric acid. 10. Process according to claim 1, characterized in that the step c. the crude sennosides obtained by brystallization to about 10% in an acetone / water mixture (50/50), dissolve completely by adding NaOH to pH 7.5-9 with sodium salt formation, the sennosides by adjusting the solution with hydrochloric acid to pH 1, 5-2 again. precipitate, separate, wash with acetone / water and dry. A method for preparing or manufacturing a pharmaceutical preparation with a laxative effect, characterized in that a product is obtained for this purpose, obtained according to the method of any one of the preceding claims. 20 8204531