DK169075B1 - Method for extracting laxative compounds from mustard drugs - Google Patents

Description

0 in DK 169075 B1

The invention relates to a particular method for recovering laxative compounds from the mustard drug.

The mustard drug consists of the dried leaves and pods of the mustard plant, e.g. the Indian senna (Cassia angustifolia) and the 5 Egyptian senna Cassia Acutifolia). The laxative effect of the mustard drug depends on a group of chemical compounds, the sennosides.

The laxative active substances in the late drug are bimolecular glycoside derivatives of the two anthracene compounds rhein and 10 aloe emodin. Most important are the late pages A, B, A ^, C and D. The late pages A, B and A ^ are bis-glycosylrheinanthrons, while the late pages C and D are glycosylrhein-glycosylaloeemodine-dianthrone compounds.

15 In addition to the sennosides, the crude drug also contains aglucones (sennidines) and other degradation products and derivatives of the sennosides. These appear partially laxative, but can also be toxic and produce undesirable side effects. Among the side effects that are typical of latex preparations, 20 may be, feeling sick, vomiting, "stomach air", colic and diarrhea.

Various methods for extracting the laxative from the mustard drug have been described. The 25 most important laxative glucosides, sennosides A and B, were first isolated from the mustard drug by Stoll et al., Helvetica Chimica Acta XXXII, Fasciculus VI (1949) 1892. Subsequently, several patents have been published describing methods for the preparation of sennoside concentrates.

In the known methods which constitute the state of the art, the preparation of the mustard extract is generally carried out in two steps. In the first step, plant pigments, fats and other contaminants are removed with a suitable solvent, e.g. chloroform, ether (US-PS 3,089,814) or with 90% of DK 169075 B1 2 methanol (DE-AS 1,617,667).

After this preliminary extraction, in the second step, the active glucosides are extracted with methanol, methanol-water, ethanol-water or with water from the drug alone.

5 To facilitate the extraction, the methanol used can be made alkaline by the addition of organic bases (DT-PS 23.397).

The organic bases form with the sennosides salts that are soluble in methanol and can be easily extracted. A disadvantage of this process is that the extract has a higher content of contaminants.

Extraction solvents which have been acidified with citric acid (FR-PS M6611 (1969)) or with oxalic acid (GB-PS 832.017) have also been proposed.

In the latter case, 70% ethanol is used as the solvent. When used for extraction, acid methanol or acid. mixture of methanol and water, the content of contaminants in the extract is less than in the case where the extraction is carried out with basic solvents or with water alone. These methods, however, are beset with the lack of the sennosides, which are acidic compounds, which free acids exhibit only poor solubility in the solvents used. Therefore, the amount of solvent required for the extraction is very large and can range from 15 to 30 times the weight of the drug used.

As the solvent in the extraction of the drug, it is also known to use phosphoric acid-acidified methanol-tetrahydrofuran, methanol-dioxane and tetrahydrofuran-dioxane mixtures (Hung. Teljes 6006 (1973)) and water (DE-AS 1,617,667).

However, these solvents activate the glucosidase enzymes so that some of the active glucosides are hydrolyzed, especially when working in weakly acidic solutions whose pH value corresponds to the pH of the original plant material. This results in a reduction of the amount of active substance in the extract, cf. also DE-OS 2,915,063.

In the methods representing the state of the art, extraction of the sennoside concentrates from the extracts is carried out in various ways.

5 A solid sennoside-containing concentrate can be prepared by gentle drying of the extract (DE-AS 1.617.667). In this case, the product contains all the substances contained in the extract. The product's sennoside content is approx. 17-18%.

However, the senosides can be separated in a more selective manner if they are precipitated from aqueous solutions with the addition of organic solvents. The resulting product contains fewer ballast substances and exhibits a sennoside content of up to 60-70%. The precipitation can be made by the addition of diethyl ether (FR-PS M 6611, Magyar G. et al.

15 Hung Teljes 6006 (1973)), isopropyl alcohol after treatment with highly acidic ion exchange resin (GB-PS 832.017) or ethanol (Finnish Patent No. 41,588). Optionally, in the dissolved state, the sennosides can be converted to the calcium salts (U.S. Pat. No. 3,089,814 and Finnish Patent 41,588) and then precipitated by the addition of organic solvents so that the effective glycosides appear as calcium salts. The sennoside content of the precipitated product in this case amounts to approx.

60-70%.

For the extraction of pure sennosides as free acids, the sennosides are isolated as calcium salts which are digested with oxalic acid (Stoll et al. Helvetica Chimica Acta XXXII, Fasciculus VI (1949) 1892).

Accordingly, according to the prior art methods, extracts 30 and various kinds of concentrates containing laxatively active substances can thus be prepared from the mustard drug. The amount of laxative active substances in the concentrates depends on the content of these substances in the original drug and on the method of preparation. The difficulty in standardizing the mustard preparations consists in the determination of the latex glycosides. The drug contains various compounds which are included in the determination of the senna glycosides. However, the physiological effect of these individual compounds is not the same. Since by conventional methods of determination it is not possible to distinguish the senaglycosides from the other compounds which have other physiological and side effects, it is difficult to make preparations which always produce 10 the usual senna extracts on the basis of the usual senna extracts. same and reproducible effect with the same dose.

It is an object of the invention to provide a method for the preparation of laxative compounds from the mustard drug by which it is possible to recover the laxatives. active substances from the mustard drug in the most concentrated form and as much as possible free of components with undesirable side effects, to obtain an improved yield.

This object is achieved by a process which according to the invention is characterized by a) extracting the mustard drug in countercurrent percolation with methanol at a concentration of 60-70% at a temperature of 25-35 ° C and concentrating the extract at a temperature of 25 to 50 ° C until the methanol is completely removed from the extract and the resulting concentrate is optionally preserved by the addition of butanol-2; b) the resulting concentrate is purified by continuous liquid / liquid extraction with an organic solvent in 30 form (c) transferring the resulting raffinate to a crystallization apparatus and, with stirring, acidifying to a pH of about 1.5-2.0, are seeded with sennoside crystals and crystallized with stirring and the resulting crude endosides are isolated, and d) the crude endosides, if desired, recrystallized and optionally converted with a pharmaceutically acceptable base to a pharmaceutically acceptable salt.

DK 169075 B1 5

Characteristic data.

For carrying out the process of the invention, methanol is used at a concentration of 60-70% in which the sennosides 5 are well soluble. Preferably, 70% methanol is used since the solubility maximum of the sennosides is at methanol concentrations of from 60 to 70%. The extraction is carried out portionwise and at slightly elevated temperatures between 25 and 35 ° C. Since there is a risk of splitting the senosides, elevated temperatures have previously been avoided. However, it has surprisingly been found that the Sennoids are not cleaved at slightly elevated temperatures if methanol is used as the solvent.

Extraction of the drug is performed in a countercurrent percolation plant. Generally, from 2 to 4 percolators are used. If the extraction solvent is to be heated, it is circulated through an external heat exchanger in which it is heated to the desired temperature, but not more than 35 ° C.

20 The more percolators used, the less the solvent must be heated. In this case, the resulting extract contains fewer harmful pollutants and the sennosides completely crystallize from the parent solution.

25

Prior to extraction, the dried drug may optionally be swollen in a solvent, preferably using a post-leachate from a previously extracted drug. To this end, place the dry drug in a percolator, cover it with a perforated plate weighing about 10 oz. 0.7 kg / dm 2 and introduces the solvent respectively the post-leachate. The weight of the required amount of solvent is approx. three times the amount of weight of the dried drug. It is preferred to leave the drug and solvent, respectively, after the leachate overnight, with the extraction being started the next day.

0 DK 169075 B1 6

Extraction takes place over 16 to 20 hours. During this time, the required amount of 70% methanol is allowed to flow through the drug mass. If it is appropriate to use multiple leachates, the solvent is first extracted at the extraction to the leachate leachate containing the weakest drug, i. the already most extracted drug and which is in line for emptying next time. From this percolator, the solvent is passed to the next percolator, etc. The main extract is taken from the last percolator that was last filled. After extracting the appropriate amount of extract, a further post-leachate is further recovered to allow the new, dry drug to swell therein. To this end, the percolator is emptied with the weakest drug, filled with a portion of the drug, after which the post-leachate is introduced and the extraction is performed the next day.

In the process of the invention, it is possible to extract one part of dry drug with only four parts of extraction solvent. If 70% methanol is used at room temperature, the residual amount in the drug is approx.

40% for each percolator in the percolator series. With two percolators 2 extraction yields (1-0.41) x 100 = 83%, 3 and with three series connected percolators (1-0.41) x 100 = 93%. 25

After the extraction, the methanol is virtually quantitatively removed from the leachate, with the volume of the resulting base product being 1/5 of the leachate volume. To remove the methanol, it is distilled off by means of a vacuum distillation apparatus equipped with a fractionation column. Due to the risk of hydrolysis of the sennosides, the temperature should not exceed 50 ° C. The resulting concentrate is optionally preserved with 5% butanol-2.

After distilling off the methanol, the concentrate is purified by liquid / liquid extraction with 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. Preferably, butanol is used as the solvent. The liquid / liquid extraction is carried out as a continuous process in a distribution apparatus having a separating effect corresponding to approx. to the theoretical steps. The pH of the concentrate solution added is about 5.4 to 5.6.6. At this pH, the salts of the late-drug aglucon compounds will hydrolyze to such an extent that the aglucones are removed virtually quantitatively from the raffinate.

Preferably, the butanol-2 used in the extraction is saturated with water before use. The concentrate added to be extracted constitutes a highly concentrated solution with a solids content of approx. 20 to 30%. This solution contains salts, sugars, amino acids and other water-soluble compounds derived from the plant mass. The extraction is preferably carried out in such a way that the outlet ratio of butanol-2 to raffinate is from 0.7: 1 to 0.8: 1.

The liquid / liquid extraction removes fats, harmful plant pigments, chlorophylls and carotenoids, free fatty acids, steroids, agluconic anthracin derivatives, neutral glucosides, plant waxes and wax alcohols, flavones and other phenols, etc. from the solution. Hereby, the resulting raffinate is released from harmful impurities to such an extent that after acidification with a mineral acid to a pH of about 1.5 to 2.0, the majority of the senosides crystallize from the raffinate phase. Hydrochloric or sulfuric acid is preferably used as mineral acid.

In order to crystallize the sennosides from the raffinate phase, these are introduced into a container and, with stirring, acid is introduced into the liquid until the pH of the solution is approx. 1.5 to 2.0. The solution is then seeded with senoside crystals. and given the opportunity to crystallize for 35 a week with stirring.

0 DK 169075 B1 8 On the other hand, it is also possible to carry out the crystallization in a continuous working crystallization apparatus. In this case, the refinement phase stays for about a week in this crystallization apparatus, thereby dividing 5 into two or more in a series of interconnected containers which open into a decanter. In the crystallization vessels, a slight stirring is constantly carried out, and to acidify the solution, the mineral acid is added while stirring in the first vessel. The vertical laminar flow in the containers is approx. 0.3 to 0.4 ml / min. This flow rate guarantees a satisfactory sedimentation. The crystallized product is filtered off, washed with water and methanol or acetone and then dried. Optionally, the crude product may be recrystallized, as will be explained in more detail below.

If desired, the crude endosides obtained after crystallization can be recrystallized. For this purpose, the raw endosides are preferably suspended in an amount of about 20 Ca. 10% in a mixture of acetone and water (50:50), dissolved by adding NaOH to a pH of 7.5 to 9 to form sodium salts, after which the sennosides are again precipitated by adjusting the solution with hydrochloric acid to a pH of 1.5 to 2, separated, washed with acetone / water 25 and dried.

Thus, with the method of the invention, it is possible to recover the sennosides from the crude drug in a purity of almost 100%. Furthermore, in the method of the invention for the extraction of laxative active substances from the late drug, it is no longer necessary to perform a preliminary fractionation of the drug, as is necessary in the methods which represent the state of the art.

Since the sennosides derived from the practice of the process of the invention are completely chemically and pharmacologically characterized, they can be used for formulating medicinal compositions with certain galenic properties. In contrast, by the known methods it is only possible to obtain more or less undetermined galenic extracts.

The following examples serve to illustrate the method of the invention.

Example 1 - * - 0 In each of two consecutively connected percolators with a volume of 250 l, 40 kg of mustard drugs are covered, which are covered with a perforated steel plate. As the solvent of the extraction, 70% methanol is used, which is fed to the drug in the first leachate. A bottom plate coated with a filter cloth is placed in the bottom of the percolator.

Through a drain tap located beneath this plate, the solution is passed to the drug placed in the second percolator. Below, the solvent is given the opportunity to flow freely through the first leachate. Below, the solvent is passed through a siphon from the first percolator's drain cock to the second percolator. The flow rate of the solution is set by means of the drain tap on the first percolator. The outlet of the second percolator is set so that the solvent in the second percolator is high enough to cover the perforated steel plate weighing 0.7 kg / dm.

For the extraction of 40 kg mustard drugs, a total of 160 liters of solvent are used. After this volume of 70% methanol has been passed through the two leachates and the corresponding amount of leachate has been collected, the leaching tube of the leachate is interconnected with a post leachate vessel, and an additional 60 l 70% of methanol is conducted. through the percolators. Then, the remaining free solvent is passed from the first leachate to the upper portion of the second leachate and the leachate is collected until it totals 120 1. Then the first leachate is emptied, charged to new with 40 kg of mustard drug, after which the post-leachate is pumped out on the drug, with 120 l of post-leachate sufficient to cover the drug in the leachate.

In addition, a hose connection is formed from the outlet to a pump and a heat exchanger and thence to the percolator's cover, the solution being circulated until its temperature is 30 ° C. It all stands overnight.

The next day, this leachate is connected to the previously extracted and the extraction is performed as described above.

For every 40 kg of drug, 160 l of leachate is collected from which the methanol is removed in a vacuum rotation evaporator equipped with a filler body column. This results in approx.

30 liters of bottom product, as a 10 step mixer settler, is extracted with 40 liters of butanol-2, saturated with 20 water. This yields about 38 to 40 liters of aqueous raf finate and about 30 to 32 liters of butanol-2 extract. The aqueous raffinate is acidified with 93% sulfuric acid with stirring for 20 hours, using 1.6% by volume calculated on the volume of the liquid to be acidified. The acidified solution 25 then has a pH of from 1.5 to 2.0. It is further stirred for 6 days, after which 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 for each 40 kg of raw material is from 760 to 790 g of dry matter with a senoside content of between 90 and 94%. The yield thus amounts to approx. 70% of the amount of sennoside present in the raw material.

35 0.5 kg of crude product is suspended in 5 L of acetone / water mixture 1: 1, with stirring, 48% sodium hydroxide solution is added until the pH of the solution is between 8.5 and 9, whereupon the unresolved DK 169075 B1 11 residue filter and add concentrated (35%) hydrochloric acid to the filtrate until the pH of the solution is 1.5 to 2. Stir until crystallization begins and allow to continue for at least 3 hours. The precipitate 5 is filtered off by the solution, washed on the filter with 0.5 l water and 0.5 l acetone and dried at room temperature in an air stream. 1/5 of the parent solution can be added to wash water and acetone, this solution being used as crystallization solvent for the next equal 10 large portion of the crude product. Yield for each 0.5 kg of crude product is 0.460 kg of dry matter with a sennoside content of between 98 and 99%.

Example 2 15 Proceed in the same manner as in Example 1, but three are used in a series of interconnected percolators and the 70% methanol is not heated. Incidentally, the process is carried out as in Example 1, using 160 liters of solvent for every 40 kg of drug. For every 40 kg of drug, 20 0.890 kg of sennoside raw product with a sennoside content of 92% solids is obtained. The crude product can be recrystallized as mentioned in Example 1.

Example 3 The extraction, the removal of the methanol from the extract and the liquid / liquid extraction are carried out as described in Example 1. After treatment with butanol-2, the sennoside mixture is crystallized from the raffinate in a continuous working crystallization apparatus. For crystallization 30, two interconnected containers and a third container are used as decants connected in series with the other. In the latter vessel, the sedimentation of the sennoside mixture is carried out, whereby most of the precipitate is separated from the parent solution. To this end, the raffinate phase obtained after purification with butanol-2 is introduced into the first vessel at a flow rate of approx. 2 1 pr. hour. At the same time, in 'DK 169075 B1 12 0 it is pumped 93% sulfuric acid in an amount of 1.6% by volume of the raffinate. In order to prevent sedimentation at this site, a continuous stirring of the liquid is carried out in the first vessel. Then, the suspension 5 is passed from the first container over a free overflow into the second container, which is also equipped with a stirrer, and from this over a free overflow to the third container, where the precipitate is given the opportunity to deposit, again the mother solution. is passed through a free overflow to 10 a waste solution container. Through a bottom-mounted tap, the precipitate is taken from the third decanter as a thick suspension, which is filtered off with a suction filter, washed with water and methanol and dried at room temperature in an air stream. The yield for each 40 kg of raw material used is 15 790 g with a sennoside content of 91%.

EJtsémpei 4

The extraction, liquid / liquid extraction and recrystallization described below are schematically depicted in FIG. 1 to 3.

The drug is subjected to extraction in a 4-stage countercurrent percolation plant at room temperature. For this purpose, 40 kg of bellows bellows are placed each day in one of four conical 25 round bins and loaded with a perforated plate.

Then, as much 70% methanol is run countercurrently through the battery of four conical round bins that the newly filled pods are completely covered with liquid. After a maceration period of at least 12 hours, percolation is continued so long that a total of approximately 160 1 70% methanol has been passed through. From the container to which the fresh solvent has been filled, the extract liquid is then fed completely to the post-coupled container and the extraction residue is dried to recover the solvent. The container is now available to take up the next 40 kg portion of DK 169075 B1 13 0 and thus be replaced at the end of the battery. The efficiency of extraction in each percolation step is about 60%. For every 40 kg of mustard bellows, about 120 liters of primary extract is obtained, which is concentrated to approx. 30 l under vacuum in a rotary evaporator rotary evaporator. The temperature in the room or rooms in which the product is located must not exceed 50 ° C.

In order to avoid disruption in subsequent liquid / liquid extraction, it is necessary to completely remove the methanol. A test is then made as to whether the concentrate is free of methanol (GC) and in addition approx. 2% butanol-2. The pH of this extract concentrate is about 5.8.

15

For the purpose of subsequent liquid / liquid extraction, the concentrate is fed into a 10-step mixer battery, each of approx. 5 1, without prior filtration against butanol-2. At an inlet ratio of butanol-2 to extract concentrate of 1.5: 1, the ratio of butanol-2 extract to extract refinate is between 0.7: 1 and 0.8: 1. The average residence time in each step is approx. 20 minutes.

The resulting extract refinate is then adjusted with 94% sulfuric acid to a pH of approx. 2 and introduced into a three-step crystallization apparatus.

The crystallization is started by grafting and then proceeds at room temperature for approx. 5 days. The resulting 30 crystal porridge is drained from the bottom of the third crystallization vessel. The bottled crystal porridge is aspirated and the mother liquor is returned to the crystallization apparatus.

The crystals are then washed with water, and then with methanol, and then dried in vacuo at 40 ° C. There are crude nanosides with a purity of approx. 90%. For the purpose of recovering butanol-2, a complete concentration of the butanol-2 extract is made, resulting in a dark brown to black residue. The distillate is again fed to the liquid / liquid extraction.

5

Then, the resulting raw endosides are suspended in an amount of about 10% in a mixture of acetone and water (50/50) and dissolved completely with the addition of sodium hydroxide solution to a pH of about 7.5 to form sodium salts.

Then, by setting the pH of the solution to 2, the senosides are precipitated to 2 by hydrochloric acid, whereupon the precipitated product is separated, washed briefly with acetone water and dried. In this way, calculated on the applied bellows, approx. 2% pure Sennosides (A and B).

15

Claims (8)

A process for the extraction of laxative compounds from mustard drugs, characterized in that: a) the mustard drug is extracted in countercurrent percolation with methanol at a concentration of 60-70% at a temperature of 25-35 ° C and the extract is concentrated at a temperature at a maximum of 50 ° C until the methanol is completely removed from the extract and the resulting concentrate is optionally preserved by the addition of butanol-2; b) the resulting concentrate is purified by continuous liquid / liquid extraction with an organic solvent in the form (c) transferring the resulting raffinate to a crystallization apparatus and, with stirring, acidifying to a pH of about 1.5-2.0, are seeded with sennoside crystals and crystallized with stirring, and the resulting crude endosides are isolated, and d) the crude endosides, if desired, are recrystallized and optionally converted with a pharmaceutically acceptable base to a pharmaceutically acceptable salt. Process according to claim 1, characterized in that 70% methanol is used as extractant in step a). 25 Process according to claim 1 or 2, characterized in that the extraction in step a) is carried out at a slightly elevated temperature of not more than 35 ° C. Process according to claims 1-3, characterized in that 5% butanol-2 is added as the preservative to the concentrate obtained in step a). Process according to claim 1, characterized in that as organic solvent in the form of partially soluble alcohols or ketones in step b), DK 169075 B1 is used butanol, methyl ethyl ketone or methyl isopropyl ketone. Process according to claim 5, characterized in that water-saturated butanol-2 is used. 5 Process according to claim 6, characterized in that the outlet ratio of butanol-2 to raffinate is from 0.7: 1 to 0.8: 1. Process according to claim 1, characterized in that the raw endosides obtained in step c) are suspended for the purpose of recrystallization in an amount of approx. 10% in an acetone / water mixture (50/50) and dissolve completely by adding NaOH to a pH of approx. 7.5 to 9 under sodium salt formation, after which the sennosides are precipitated again by adjusting the pH of the solution by means of hydrochloric acid to a pH of approx. 1.5-2, after which they are isolated, washed with acetone / water and dried.