FI75992B - FOERFARANDE FOER UTVINNING AV LAXATIVA FOERENINGAR UR SENNADROG. - Google Patents

Description

1 75992

Method for the recovery of laxatives from Senna rohdoks - Förfarande för utvinning av laxativa föreningar ur sennadrog

The invention relates to a method for recovering laxatives from senna herb.

Senna herb consists of dried leaves and pieces of senna plants, such as Indian Senna (Cassia angustifolia) and Egyptian Senna (Cassia ecutifolia). The laxative effect of senna herb is due to a chemical compound, sennoside.

The laxative active ingredients of senna herb are bimolecular glycoside derivatives of both anthracene compounds, rain and aloe emodin. The most important are sennosides A, B, Αχ, C and D. Sennosides A, B and Ai are bis-glucosyl-rain anthrons, sennosides C and D are glycosylline-glycosylaloe-emodine dianthrone compounds.

In addition to sennosides, the raw herb also contains aclone machines (sennidines) and other sennoside decomposition products and derivatives. Hills have a partially laxative effect, but can also be toxic at the same time and cause unwanted side effects. These side effects, which are typical of senna products, include malaise, vomiting, bleeding, colic, and diarrhea.

Various methods have been described for the extraction of laxatives from senna herb. The main laxative glycosides, sennosides A and B, 2 75992 were first isolated from senna herb by Stoll et al., Helvetica Chimica Acta XXXII, Fasciculus VI (1949) 1892. Since then, several patents have been published describing methods for preparing sennoside concentrates.

In the known methods according to the prior art, the preparation of the extract is generally carried out in two steps.

In the first step, the plant pigments, fats and other impurities are removed as a suitable solvent, e.g. chloroform, ether (US-A 3,089,814) or 90% methanol (DE-AS 16 17 667).

After this pre-extraction, in a second step, the active glucosides are extracted from the herb with methanol, methanol-water, ethanol-water or water only.

To facilitate the extraction, the methanol used can be made alkaline by adding bases (DE-A-23 397). Organic bases form methanol-soluble salts with sennosides which can be easily extracted. The disadvantage of this method is that the extract contains more impurities.

It has further been proposed to use an extraction solvent acidified with citric acid (FR-A M6611 (1969)) or oxalic acid (GB-A-832 017). In the latter case, 70% ethanol is used as the solvent. When acidic methanol or an acidic mixture of methanol and water is used for the extraction, the extract contains fewer impurities than if the extraction is carried out with basic solvents or with water only. However, the disadvantage of these methods is that the sennosides, which are acidic compounds, are sparingly soluble in the solvents used.

Therefore, the amounts of solvent required for extraction are

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3 75992 very large and are 15 to 30 times the weight of the herb used.

It is further known to use methanol-tetrahydrofuran, methanol-dioxane and tetrahydrofuran-dioxane mixtures acidified with phosphoric acid (Hung. Full 6006 (1973)) and water (DE-AS 16 17 667) as solvent in herbal extraction. However, these solvents activate glucosidase enzymes, thereby hydrolyzing some of the potent glucosides, especially when operating in weakly acidic solutions having a pH similar to that of the original plant material. This reduces the amount of active ingredient in the extract, see also DE-OS 29 15 03.

In prior art methods, sennoside concentrate is recovered from extracts by various routes.

The solid, sennoside-containing concentrate is obtained by carefully drying the extract (DE-AS 16 17 667). The product then contains all the substances in the extract. The sennoside content of the product is about 17-18%.

However, senocides can be selectively separated when it is precipitated from aqueous solutions by the addition of organic solvents. The product obtained contains less unnecessary substances and has a sennoside content of up to 60-70%. Precipitation can be performed by adding diethyl ether (FR-A M6611, Magyar G. et al. Hung. Full 6006 (1973)), isopropyl alcohol after treatment with a strongly acidic ion exchange resin (GB-A 832 017) or ethanol (Finnish Patent 41,588). Sennosides can optionally be converted in solution to calcium salts (US-A 3,089,814, Finnish Patent 41,588) and subsequently precipitated by the addition of organic solvents to give the effective glucosides as 4,75,992 calcium salts. The content of senosides in the precipitated product is then about 60-70%.

To obtain the pure sennosides as free acids, the sennosides are isolated as calcium salts and these salts are decomposed with oxalic acid (Stoll et al. Helvetica Chimica Acta XXXII,

Fasciculus VI (1949) 1892).

DE-A-10 32 888 and GB-A-804 232 disclose processes for the separation of sennosides in which the extraction medium is a methanol solution at normal temperature. However, the product obtained in the form of a salt has a sennoside content of only about 30%.

These prior art methods can thus be used to prepare extracts and concentrates of various qualities from senna herb which contain laxative active substances. The amount of laxative active substances in the concentrates depends on the concentration of this compound in the original herb and the method of preparation. A difficulty in standardizing senna preparations is the determination of senna glycosides. The herb contains various compounds that are involved in the determination of sennaglucosides. However, the physiological effect of these individual compounds is not always the same. Because it is not possible to distinguish sennaglucosides from other compounds with other physiological effects and possibly side effects by conventional assay methods, it is difficult to prepare preparations from conventional sena extracts which always give a similar and reproducible effect at the same dose.

It is an object of the present invention to provide a process for recovering laxative compounds from senna 5 75992, in which the laxative active substances of senna herb are recovered in the most concentrated form and as free as possible from components having undesirable side effects in better yields.

This object is achieved according to the invention by a process characterized in that a) the senna herb is extracted with a methanol / water mixture by countercurrent percolation and the extract is evaporated at <50 ° C until the methanol has completely removed from the extract, b) the obtained concentrate is purified by continuous liquid-liquid by extraction as an organic solvent, c) the obtained raffinate is passed to a crystallization apparatus and acidified with stirring to a pH of about 1.5 to 2.0, seeded with sennoside crystals, allowed to crystallize with stirring and the obtained crystalline crude sennosides are separated, d) the crude sennosides are recrystallized if desired. Characteristic values

Mixtures of methyl alcohol and water in which the sennosides are soluble are used to carry out the process according to the invention. 70% methanol is best used because the maximum solubility of sennosides is 60-70% at methanol concentrations. The extraction is carried out very and preferably at slightly elevated temperatures, but not more than at a solvent temperature of + 35 ° C. Due to the risk of decomposition of sennosides in the past, elevated temperatures of 75992 Ό have been avoided. Surprisingly, however, it was found that sennosides do not decompose at slightly elevated temperatures when methanol is used as the solvent.

The herb is extracted in a countercurrent percolation apparatus. Usually 2-4 percolators are used. If the extraction solvent needs to be heated, it is allowed to circulate through an external heat exchanger and is then heated to the desired temperature, but not more than 35 ° C. The more percolators used, the less solvent needs to be heated. The extract obtained then contains less harmful impurities and the sennosides crystallize completely from the mother liquor.

Before extraction, it is recommended to allow the dry herb to swell in a Liu receiver, in which case the post-percolate obtained from the already extracted herb is best used. To this end, the dry herb is placed in a percolator, covered with perforated plates weighing about 0.7 kg / dm 2, and a solvent or post-percolate is introduced. The weight of the required amount of solvent is about three times the weight of the dry herb. Allow to stand best overnight and start the extraction the next day.

Extraction takes place within 16-20 hours. During this time, the required amount of 70% methanol is passed through the herb mass. Since it is expedient to use several percolators, the extraction solvent is first passed to the percolator of the percolator set which contains the weakest herb, i. already the most extracted herb, and which will be emptied next. From this percolator, the solvent is passed to the next percolator, etc. The main extract is removed from the percolator that was last filled. After removal of a suitable amount of extract, a further percolate is obtained, in which the new, dry herb is allowed to swell. To do this, the percolator containing the weakest herb is emptied, filled with a batch of herbs, the post-percolate is introduced and the extraction is carried out the next day.

In the method according to the invention, it is possible to extract one part of the dried herb with only four parts of the extraction solvent. If 70% methanol is used at room temperature, the amount of residue in the herb is about 41% per percolator of the percolator array. When two percolators are used, the extraction yield is o (1-0.41) x 100 = 83% and when three percolators connected in series (1-0.41 ^) x 100 = 93%.

After extraction, the methanol is virtually completely removed from the percolate, resulting in a volume of about 1/5 of the volume of the percolate base product. To remove methanol, this is distilled using a vacuum distillation apparatus equipped with a fractionation column. Due to the risk of hydrolysis of sennosides, the temperature must not exceed 50 ° C.

After the methanol is distilled off, the concentrate is purified by liquid-liquid extraction as an organic solvent. Partially water-soluble alcohols and ketones such as butanol, methyl ethyl ketone and methyl isopropyl ketone can be used as organic solvents. The most commonly used solvent is butanol-2. Liquid-liquid extraction is carried out as a continuous process in a distributor with a separation effect of about 10 theoretical steps. The pH of the feed concentrate solution is then about 5.4-5.6, because at this pH the salts of the aglucone compounds in the senna herb are hydrolyzed to such an extent that the aglucones can be removed from the raffinate practically quantitatively.

The butanol-2 used in the extraction is best impregnated with water before use. The concentrate fed, which must be extracted, is a very concentrated solution with a dry matter content of about 20-30%. It contains salts, sugars, amino acids and other water-soluble compounds derived from vegetable pulp. The extraction is performed with a butanol-2: raffinate removal ratio of about 0.7-0.8: 1.

Liquid extraction removes from the solution fats, harmful plant pigments, chlorophylls and carotenoids, free fatty acids, steroids, agluconic anthracene derivatives, neutral glucosides, vegetable waxes and vegetable alcohols2, as well as after acidification with mineral acid to a pH of about 1.5-2.0, precipitates directly from the raffinate phase. Hydrochloric or sulfuric acid is best used as the mineral acid.

To crystallize the senosides from the raffinate phase, this is placed in a tank and introduced into the liquid with stirring so much acid that the pH of the solution is about 1.5-2.0. The solution is then seeded with sennoside crystals and allowed to crystallize for one week with stirring.

Crystallization can also be performed in a continuously operating crystallization apparatus.

The raffinate phase remains in this crystallizer for about one week divided into two or more series of connected tanks connected to a decanter. In the crystallization tanks, the mixture is gently stirred all the time and the solution is acidified by adding mineral acid to the first tank while stirring. The vertical laminar flow in the tanks is then 0.3-0.4 mm / minute. This flow rate ensures satisfactory sedimentation. The crystalline product is filtered off, washed with water and methanol or acetone and dried. Optionally, the crude product is recrystallized as explained below.

The crude sennosides obtained after crystallization can be recrystallized if desired. Preferably, the crude sennosides are suspended in about 10% acetone / water (50:50), dissolved by the addition of sodium hydroxide to about pH 7.5-9 to form sodium salts, and the sennosides are reprecipitated by readjusting the solution to about 1.5 -2, separated, washed with acetone / water and dried.

With the process according to the invention, it is thus possible to recover the sennosides from the crude herb in almost 100% purity. In order to recover laxatively active substances from senna herb, it is no longer necessary to use any herb pre-extraction in the process according to the invention, as has been necessary in the prior art processes.

Since the sennosides obtained by the process according to the invention have been completely characterized chemically and pharmacologically, they can be used for the formulation of pharmaceutical preparations with certain caleneic properties. In contrast, the method according to the prior art can only obtain more or less vague kalenic extracts.

The following examples further illustrate the method of the invention.

Example 1

To two percolators connected in series with a capacity of 250 liters, 40 kg of senna herb is added to each and covered with a perforated steel plate. The solvent of the extraction is 70% methanol, which is passed over the herb of the first percolator. The bottom of the percolator has a base plate covered with a filter cloth. Through a drain tap installed under this plate, the solution is passed over the herb in the second percolator. In this case, the solvent is allowed to flow freely through the first percolator. The solvent is then passed from the discharge tap of the first percolator to the second percolator by means of a shovel. The solution flow rate is controlled by the first percolator drain cock. The discharge flow of the second percolator is adjusted so that the solvent of the second percolator is so large that it covers the perforated steel plate with a weight of 0.7 kg / dm.

A total of 160 liters of solvent is used to extract a 40 kg batch of senna herb. After this volume of 70% methanol has been passed through each percolator and the corresponding amount of percolate has been obtained, the percolator drain hose is connected to a post-percolate tank and a further 60 liters of 70% methanol are passed through the percolators. The remainder of the free solvent is then passed from the first percolator to the top of the second percolator and the post-percolate is collected until a total of 120 liters is obtained. The first percolator is then emptied, refilled with 40 kg of senna herb, and the post-percolate is pumped onto the herb, with 120 liters of post-percolate being sufficient to cover the herb in the pergolator. A flow is then provided from the hose connection to the pump and heat exchanger and from there to the percolator cover and the solution is circulated until the temperature of the solution is 30 ° C. It is then allowed to stand overnight.

The next day, this percolator is combined with the already extracted percolator and the extraction is performed as described above.

For each batch of 40 kg of herbs, 160 liters of percolate are obtained, from which the methanol is removed in a vacuum rotary evaporator equipped with a packed column. About 30 liters of bottom product are obtained, which is extracted in a "Mixer-Settler" (10 steps) with 40 liters of water-saturated butanol -2. About 38-40 liters of aqueous raffinate and about 30-32 liters of butanol -2 extract are obtained. The aqueous raffinate is acidified with 93% sulfuric acid for 20 hours with stirring, the amount used being 1.6% by volume (based on the volume of liquid to be acidified). The pH of the acidified solution is then 1.5-2.0. Stir for a further 6 days, allow the precipitate to settle overnight, filter, wash with water until the washings are colorless, wash with methanol and dry in a stream of air at room temperature. From 40 kg of raw material, 760-790 g (dry matter) of product with a sennoside content of 90-94% are obtained. The yield is thus about 70% of the amount of sennoside in the raw material.

0.5 kg of crude product is suspended in 5 liters of a mixture of acetone and water (1: 1), 48% sodium hydroxide is added with stirring until the pH of the solution is 8.5-9, the insoluble residue is filtered off and concentrated (35%) hydrochloric acid is added to the filtrate. until the pH of the solution is 1.5-2. Stir until crystallization begins and then allow to crystallize for at least 3 hours. The precipitate is separated from the solution by filtration, washed as a filter with 0.5 liters of 75992 l of water and 0.5 liter of acetone and dried at room temperature in a stream of air. Wash water and acetone can be added to 1/5 of the mother liquor and this solution is used as the crystallization solvent for the next equal batch of crude product. A yield of 0.460 kg (dry matter) with a sennoside content of 98-99% is obtained from 0.5 kg of crude product.

Example 2

Proceed as in Example 1, but use three percolators connected in series and 70% methanol is not heated. Otherwise proceed as in Example 1 and use 160 liters of solvent per 40 kg of herb. From a 40 kg herb, 0.890 kg of crude sennoside product with a sennoside content of 92% (dry matter) is obtained. The crude product can be recrystallized in the same manner as in Example 1.

Example 3

Extract, remove methanol from the extract and perform liquid-liquid extraction as described in Example 1. After the butanol-2 treatment, the sennoside mixture is crystallized from the raffinate in a continuous crystallizer. For crystallization, two tanks connected in series and a third tank acting as a beaker are connected in series with the other tanks. In the latter tank, sedimentation of the sennoside mixture is carried out, for which most of the precipitate is separated from the mother liquor. For this purpose, the raffinate phase obtained after the butanol-2 purification is introduced into the first tank at a flow rate of about 2 liters / hour. This tank is simultaneously pumped with 93% sulfuric acid in 1.6% by volume of raffinate. Sedimentation at this point is prevented by constantly stirring the liquid in the first tank. The suspension is then passed from the first tank through the free overflow to the second tank, which is also equipped with a stirrer, and from there through the free overflow to the third tank, where the precipitate is allowed to settle so that the mother liquor is again passed through the free overflow to the solvent waste tank. The precipitate is removed from the third beaker 12 75992 as a thick suspension through a tap fitted to the bottom, filtered through a suction filter, washed with water and methanol and dried at room temperature in a stream of air. A yield of 790 g and a sennoside content of 91% are obtained from 40 kg of raw material used.

Example 4

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

The herb is extracted in a four-stage countercurrent percolation apparatus at room temperature. To do this, 40 kg of senna pods are placed daily in four conical round containers and covered with a perforated plate.

So much 70% methanol is then passed countercurrently through the four-coil that the freshly added fires are completely covered by the liquid. After a soaking time of at least 12 hours, it is then percolated until a total of about 160 liters of 70% methanol have passed through. From the tank filled as a new solvent, the extraction liquid is then completely passed to the next tank and the extraction residue is dried to recover the solvent. The tank is now available for the next 40 kg batch and is connected to the end of the battery. The extraction efficiency per percolation step is about 60%. For each batch of 40 kg of senna pods, about 120 liters of primary extract are obtained, which is evaporated in vacuo on a rotary evaporator equipped with a concentrator to about 30 liters. In this case, the temperatures in the product compartment must not exceed 50 ° C.

In order for the next liquid-liquid extraction to be trouble-free, the methanol must be completely removed. Determine if methanol (GC) is still present in the concentrate and then add about 2% butanol-2. The pH of this extract concentrate is about 5.8.

In the next liquid-liquid extraction, the concentrate is passed without prior filtration against the butanol-2 solvent in a 10-stage stirred separation battery (each stage about 5 liters).

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13 75992

When the butanol-2: extract concentrate feed ratio is 1.5: 1, the butanol-2 extract: extract affinity ratio is 0.7-0.8: 1. The average residence time for each phase is about 20 minutes.

The resulting extract is then adjusted to a pH of about 2 with 94% sulfuric acid and passed to a 3-stage crystallizer.

To initiate crystallization, inoculate and then allow to crystallize at room temperature for about 5 days. The resulting crystal porridge is removed from the bottom of the third crystallization tank. The removed crystal porridge is filtered 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 sediments with a purity of about 90% are obtained. The butanol-2 solvent is recovered by complete evaporation of the butanol-2 extract to give a dark brown-black residue. The distillate is again passed to liquid-liquid extraction.

The resulting crude sediments are then suspended to about 10% in a mixture of acetone and water (50/50) and completely dissolved by the addition of sodium hydroxide to about pH 7.5 to form sodium salts. The sennosides are then precipitated by readjusting the solution to pH 2 with hydrochloric acid, the precipitated product is separated off, washed rapidly with acetone-water and dried. In this way, about 2% of pure sennosides (A and B) are obtained, calculated on the pieces of sennas used.

Claims (9)

A process for recovering laxative compounds from the late drug, characterized in that a) the late drug is extracted with a methanol / water mixture by countercurrent percolation and the extract is evaporated at a temperature of ^50 ° C until the methanol is completely dispensed from the extract, b) the obtained the concentrate is purified by continuous liquid extraction with an organic solvent such as butanol, methyl ethyl ketone or methyl isopropyl ketone; c) the resulting raffinate is passed to a crystallization device and acidified with stirring to pH 1.5 - 2.0, inoculation is performed with sennoside crystals, crystallization in the solution takes place under simultaneous stirring and the obtained crystalline race endosides are separated, d) the race endosides are recrystallized as needed and optionally converted with a pharmaceutically suitable base to a pharmaceutically suitable site. Process according to Claim 1, characterized in that as 70% methanol extraction solution is used. Process according to claims 1 and 2, characterized in that the extraction in stage a) is carried out at slightly increased temperatures, at most at 35 ° C. 4. A method according to any of the preceding claims, characterized in that, before the percolation, the latexes can swell in the post-dressing. Process according to any one of the preceding claims, characterized in that in the concentrate obtained in step a) 5 percent butanol-2 is added. 6. A process according to claim 1, characterized in that the solvent in stage b) is water-saturated butanol-2. IN!