WO1991003296A1

WO1991003296A1 - Process and device for extracting fine-particle solids

Info

Publication number: WO1991003296A1
Application number: PCT/CH1990/000205
Authority: WO
Inventors: Szabolcs Nyiredi; Lajos Botz; Otto Sticher
Original assignee: Petazon Ag
Priority date: 1989-09-04
Filing date: 1990-09-03
Publication date: 1991-03-21
Also published as: EP0442987A1; CH674314A5

Abstract

Exhaustive extraction of constituents of a layer of fine-particle solids is carried out by forcing the extraction medium through the layer by the application of force. This extraction process is rapid and can be used to extract extremely fine solid particles.

Description

Method and device for extracting finely divided solids

Solid-liquid extraction is used to extract ingredients, i.e. Components of solids for preparative or analytical purposes obtained in dissolved form. Extraction technology knows two different types of processes for solid-liquid extraction. One of these types of process works until a concentration equilibrium between solution and residue is established, and the other becomes exhaustive, i.e. quantitatively extracted.

The best known and simplest method for quantitative extraction is called percolation. Percolation has gained particular practical importance for the extraction of drugs. Drugs are whole plants or parts thereof and dried animals, parts of animals or excretions of animals.

During percolation, a cylindrical or conical glass vessel, which is provided at the bottom with a tap to regulate the flow rate, and which has a sieve plate in its lower part, on which a layer of the comminuted drug, which forms the so-called drug still, lies with solvent loaded. Only fresh solvent is brought into contact with the drug. Accordingly, the consumption of solvent is high. In addition, the time to complete extraction is very long because the percolation speed is very low. According to German, for example Pharmaceutical book (DAB 8) 4 to 6 drops per minute per 100 g drug and according to USP (XXI) 0.1 to 0.5 ml per minute per 100 g drug, 0.5 ml per minute already referred to as rapid percolation becomes.

This known method must be carried out with a crushed drug that does not contain any fine particles, since the latter clog the percolator.

The comminuted drug is preferably subjected to a pre-swelling prior to percolation. Because of the risk of glass percolators bursting due to the swelling pressure, the pharmacopoeias prescribe the pre-swelling outside the percolator.

The limitation with regard to finely divided drug and the speed have a disadvantageous effect in the practical implementation of percolation, both on the laboratory and on the industrial scale. There is a further restriction with regard to solvents, since relatively more viscous solvents, such as i-propanol, butanol or water, are undesirable for percolation.

The object of the present invention is therefore to propose a method for the exhaustive extraction of ingredients from finely divided solids, in particular for the exhaustive extraction of drugs, ie percolation, in which - preferably without increasing, in particular with a reduction, the amount of fresh solvent used - can be worked with significantly higher extraction speed. This object is solved by the characterizing features of claim 1. In addition to the drugs already mentioned, ie biological matrix, finely divided solids are also understood to mean soil, ores and the like. It is essential that these solids have a proportion of extractable constituents. The extractable constituents can also be produced in situ, for example metals can be converted into salts which are soluble in the extractant by means of acidic extractants. Particularly preferred embodiments of the invention form the subject of claims 2 to 12.

When a solvent is forced through the drug layer according to the invention by means of force, ie overpressure, vacuum or centrifugal force, this layer, which is also referred to as a wick, is first compressed, ie the free spaces between the particles are minimized. This is an undesirable process in percolation according to the prior art, since it leads to undesired blockage of the percolator and, as a result, to channel formation in the drug wick. Surprisingly, these undesired processes were not observed when the extraction according to the invention was carried out. Presumably they do not occur because, according to the invention, after the compression, the solvent is still under the action of force and is forced through the drug wick by means of, preferably the same overpressure. As a result of the interspaces narrowed due to the fact that the drug wick is compressed, the solvent flows through in an extremely thin layer or in an extremely thin film between the particles, as a result of which an optimal exchange of substances occurs. Since even the smallest parts of the substance to be extracted in the wick or in the layer do not interfere with the method according to the invention, - 4 -

According to the invention, a material with a very large surface area can be extracted. When extracting biological products, the use of the finest parts has the advantage that material with broken cell walls can also be extracted. The soluble components are easily washed out, while with intact cell walls the ingredients get into the extract due to the slower diffusion through the cell walls.

With the method according to the invention, the time required for the complete extraction of a drug can be reduced to fractions of the time required for the known percolation.

Although for the sake of simplicity only drugs are mentioned, it should be emphasized that drugs are only one example of fine-particle solids that can be extracted according to the invention. Other solids extractable with the method according to the invention are soil (analysis, cleaning, extraction of substances), ores (analysis, extraction of substances).

In addition to the faster, non-clogging, quantitative extraction of any fine-particle solids with practically any particle spectrum down to a lower particle size limit of 50 μm or less, the invention also enables the use of a larger number of solvents, in particular also those with a higher viscosity . It should be emphasized that the extraction can be carried out using only a single solvent or solvent mixture or in succession using a plurality of solvents or mixtures. The extract of everyone Solvent or mixture is collected separately and worked up. The finely divided solid is preferably dried by flushing with nitrogen before using a new solvent.

Nitrogen or another inert gas can also be used to compress the particles within the layer before the solvent is applied.

If the crushing, e.g. Grinding the solids to be extracted with the addition of grinding aids, e.g. Sand, the extraction can be carried out without removing the grinding aid. An inert, finely divided solid can also be added to the finely divided solid to be extracted after grinding. As a result, the homogeneous layer formation can be facilitated and the extraction speed increased.

The completeness of the extraction can be further increased by periodically increasing or decreasing the force applied, i.e. Overpressure or centrifugal force can be improved. For example, the solvent can be forced through the drug wick at a pressure of 0.15 MPa for 3 minutes, followed by 3 minutes with less or no overpressure. During the period of high pressure with rapid solvent flow, the dissolution processes are favored, whereas the period of lower pressure with slow solvent flow or during periods with stationary solvent, in particular the diffusion processes, are favored.

Since the method according to the invention works extremely quickly and for exhaustive extraction of Materials with practically any particle size distribution, especially in front of very small particles, is suitable, it can also be used advantageously on a laboratory and also on a pilot and industrial scale. Such a process on a larger scale can be a) discontinuous absolute countercurrent extraction, in which the extractant and the drug move against one another, b) continuous relative countercurrent extraction, in which only the liquid phase moves, while the drug is in the same vessel during the entire extraction remains and c) are carried out as a continuous absolute countercurrent extraction, in which the extractant and the drug are in constant motion.

The extraction on a laboratory scale can be carried out in the chemical as well as in the clinical laboratory, whereby in the second case it is mainly extraction within the scope of the clinical analysis.

In the extraction of larger quantities of drugs, the procedure is preferably such that the drug wick (or other small-scale material), optionally after compression with nitrogen from a first solvent reservoir, is acted upon by a pump with solvent and the solvent is used with the aid of force, is preferably forced through the drug wick by means of overpressure. The solvent emerging from the drug wick and thereupon from the extraction vessel reaches a vessel for the extract, from where it is fed to a vacuum distillation system. The extract is concentrated in the vacuum distillation system and pure solvent is recovered, which is again the first Storage vessel is fed. The liquid level in the vessels can be kept at the desired level by controlling barrier elements of the corresponding lines arranged before the distillation system and after the distillation system.

Any known, e.g. cylindrical or conical vessels with single or double walls can be used. In the lower part of the vessel there is a small-pore plate, e.g. made of sintered material, on which the drug wick rests. Such a plate preferably also separates the solvent inlet from the drug wick. With double-walled vessels, the contents of the vessel can be tempered, i.e. be heated or cooled.

Since the solvents used are generally very volatile and therefore 100% recovery is not possible, the first storage vessel is preferably connected to a further third storage vessel from which the loss of solvent within the circuit is replaced.

The extract obtained, which generally consists of a mixture of different components, can be separated into its components by a chromatography step before distillation. Such a procedure is particularly advantageous for the extraction of active substances on a commercial scale, since in addition to the speed and particle size independence of the process according to the invention for obtaining a mixture of substances, there is another advantage, the separation of the substances and the Ge

- 8th -

pure substances can be obtained in the same cycle with little additional cost.

The chromatography step is carried out by introducing the extract into a chromatography column, where at least one or at most all extracted substances are adsorbed, one could also say "filtered out" from the extract, followed by elution with other solvents.

A device for carrying out the method according to the invention has the features of claim 13 and for carrying out the continuous method that of claim 14. Particularly preferred embodiments are claimed in claims 15 to 17.

The timer switches the pump on and off according to a predefined time program. The pressure regulator, which can be coupled to the time switch, ensures that the shut-off element at the outlet end of the extraction vessel is closed or opened when predetermined pressure values are reached. As a result, the pressure curve is controlled over time in the extraction vessel.

A pump without pulse heating, i.e. without equalizing the pump effect.

All parts of such a device which come into contact with the solid to be extracted and with the extract preferably consist of an inert material. Particularly good experiences have been made with systems made of glass and Teflon, with elements made of Teflon can also be replaced by te ion-coated materials.

The invention is further illustrated with the aid of the figures. It shows purely schematically:

1 and 2 each show a model of the structure of a biological matrix;

3 shows a model representation of the extraction process;

4 shows a device for the continuous implementation of the method according to the invention;

5 shows the pressure curve in the extraction vessel as a function of time.

1 and 2, the hexagonal cells 2 of the biological matrix 1, for example a drug, are delimited by cell walls. In each individual cell there are several different extractable cell constituents which are illustrated by different geometrical figures 4, 5, 6, 7. The different polarity of the cell contents is represented by different degrees of blackening. If the cell walls are closed, as shown in FIG. 1, the cell contents 4, 5, 6, 7 can only be obtained by a diffusion process taking place during the extraction, ie when the individual substances pass through the cell wall. The more finely divided a biological material is ground, the more cell walls are broken open, as can be seen from FIG. 2. The substances from cells 2 'with broken cell walls 3' can be washed out or rinsed out by a solvent without a diffusion process. This washing process takes place significantly faster than diffusion. Since in the method according to the invention it is possible to use almost any small amount of ground biological substances (since there is no risk of clogging), in the extraction according to the invention a part of the cell contents is washed out of the broken cells and only a part gets into the cell by a diffusion process Extract. Accordingly, the extraction process according to the invention works significantly faster and generally with relatively little solvent.

FIG. 3 shows the biological material 1 'already known from FIG. 2 with hexagonal cells 2' with partially broken cell walls 3 '.

If this material l ^{1 is} successively extracted with various solvents A, B, C, D of increasing polarity, an extract 11, 12, 13, 14 is extracted from the biological material 1 'with each of the solvents. The polarity of the constituents of the biological material contained in the respective extract increases with that of the solvent A to D. The individual substances in the extracts 11, 12, 13, 14 are shown in FIG. 3 by different geometric shapes and Different polarity of the fabrics illustrated by different degrees of blackening of the surfaces of the geometric shapes. It is shown that different substances (geom. Figures 4, 5, 6, 7) with similar polarities are contained in a single extract. The device 21 in FIG. 4 has a cylindrical extraction vessel 22 or a column made of glass. This is filled with a drug 23. The upper end 24 of the extraction column is connected to a line 25 which connects the extraction vessel 22 to a pump via a pressure regulating member 26. The pump 27 is in turn connected via a line 28 to a first reservoir 29 for solvent. The lower end 31 of the extraction vessel 22 is connected via a line 32 to a vessel 33 for the extract. Following the extraction vessel 22, the line 32 is provided with a shut-off element 35. This shut-off element 35 is controlled by the pressure regulating element 26. If desired, one or more chromatography column (s) can be arranged after the extraction vessel 22 before the vessel 33 for the extract.

The vessel 33 for the extract is connected via a further line 36 to a schematically illustrated vacuum distillation system 37. This vacuum distillation system has a piston 38, which is arranged in a water bath 39 and can be rotated about its longitudinal axis, and a cooler 41. Following the vacuum distillation system 37, a collecting vessel 42 for the distilled solvent is arranged. This collecting vessel is connected via a line 43 to the first storage vessel 29 for solvents.

Via a line 46, the first storage vessel 29 for solvents is connected to a second storage vessel 47 for solvents, which is closed in a pressure-tight manner. - 12 -

Floats 48, 49 are provided both in the vessel 33 for the extract and in the collecting vessel 42 for the solvent, the regulating members 44, 45, 46 assigned to them via the pressure regulating member 26 or not shown, 46a which are arranged immediately after the pump 27, in front of the distillation system and after the collecting vessel 42.

In operation, the cylindrical extraction vessel 22, after being filled with the ground drug 23, is compressed either via the application of an inert gas or with the solvent from the first storage vessel 29 via the line 25. If, after loading with the solvent, the predetermined upper limit of the pressure, e.g. 0.15 MPa is reached, the shut-off device 35 is opened by the pressure regulating member 26, so that extract can reach the vessel 33 for the extract via the line 32. If the predetermined lower limit of the excess pressure, e.g. 0.02 MPa, the pump 27 is switched off by the pressure control member 26 and the shut-off member 35 is set to the closed position. After a predetermined time, during which the main diffusion processes take place, the pump is switched on again and after reaching a predetermined upper pressure value, the shut-off device 35 is opened again. This process is repeated periodically depending on the pressure prevailing in the extraction vessel. Of course, it is also possible to work under constant overpressure.

If the float 48 indicates a certain level for the extract in the vessel 33, the line 36 is released by the shut-off device 45, so that the extract flows into the Vacuum distillation system 37 can reach. If the extract falls below a given minimum level in this vessel 33, the shut-off device 45 blocks the line 36. At the same time, the distillation is stopped. Likewise, the shut-off device 44 blocks the line 25 when a certain maximum level is exceeded. In the same way, the interaction between float 49 and shut-off device 45 takes place.

The distilled solvent passes from the vacuum distillation system 37, which has a distillation vessel 38, egg heating bath 39 and a cooler 41, in a collecting vessel 42 which is connected to the supply vessel 29 by a line 43. A float 49 in the collecting vessel 4 controls the two valves 46 and 46a at the outlet and a inlet of the collecting vessel 42.

The second storage vessel 47 is tightly closed, so that the pressure equalization via the line 50 can only follow if the solvent level in the first storage vessel 29 has fallen below a certain minimum level. At this moment, air enters line 50 and, after pressure equalization, solvent can pass through line 50 into storage vessel 29. By the solvent from this second reservoir 47 de solvent loss, which also occurs with careful work, is replaced.

The invention is further illustrated by the following example. - 14 -

example 1

Extraction of florkumarin from Heracleeum sphondylium root drug.

860 g of finely ground root drug with a broad particle spectrum (50-330 μm) were introduced into the cylindrical extraction vessel with a volume of 1230 ml (52 x 549 mm) and compressed with the inert gas nitrogen. A glass filter with a pore size of 10 m was arranged at the lower and at the upper opening of the extraction cylinder. The solid-liquid extraction was carried out continuously under pressure with chloroform. The work was carried out at a solvent rate of 60 ml / min for 6 hours.

The device used corresponded to that in FIG. 4. According to the illustration in this figure, the solvent was recovered and used again. Therefore, the exhaustive extraction, which requires a total of 21.6 liters of solvent, could be carried out with only 3 liters of solvent.

The effectiveness of the extraction was continuously monitored using thin-layer chromatography. Based on the quantitative analytical determination (G.C. Zogg, Sz. Nyiredy, 0. Sticher: Deutsche Apotheker Zeitung 129 (1989) 717) the extraction was 92% effective.

Example 2

Extraction of flavonoid glicoside fraction from Betulea pubescens leaf drug. 1650 g of ground leaf drug (particle size 320-630 μ) were introduced dry into a cylindrical extraction vessel and nitrogen was compressed under pressure of the inert gas. The extraction vessel had a volume of 2460 ml (52 x 1128 mm). A glass filter with a pore size of 10 μm was attached to its lower and upper opening. The solid-liquid extraction was started with chloroform in order to extract the apolar components. In continuous operation with a solvent speed of 40 ml / min, extraction was carried out for 8 hours. With regard to the target fraction, this stage can be regarded as pre-cleaning. This method was carried out with the device according to FIG. 4.

Thereafter, the extraction was continued using ethyl acetate as solvent to obtain the flavonoid glososide fraction. The extraction was carried out with a periodic pressure program according to the following scheme: setting 0.15 MPa overpressure, reducing the pressure to 0.02 MPa overpressure and maintaining this pressure for 10 minutes. The design was carried out by closing the outlet opening of the extraction vessel 22 by the shut-off element 35 until the pressure in the extraction vessel reached 0.15 MPa gauge pressure. Thereafter, the blocking member was opened by the pressure control member 26 according to the predetermined program, while the pump 27 continued to operate. When the pressure was reduced to 0.02 MPa gauge pressure, the pressure control element 26 switched off the pump 27 and the shut-off element 35 was closed. This pressure was then maintained for 10 minutes. During this time, the diffusion of the material to be extracted from closed cells into the solvent was particularly favored. The extraction cycle shown was repeated 32 times. - 16 -

The extract was concentrated with the rotary vacuum distillation device 37. The ethyl acetate recovered in this distillation was fed again to the extraction vessel 22.

The effectiveness of the extraction was monitored by means of thin-layer chromatography. The extraction proved to be 94% effective on the basis of the quantitative analytical determination (K. Dallenbach, Sz. Nyiredy, B. Meier, 0. Sticher: Deutsche Apotheker Zeitung 127 (1987) 1167).

Example 3

Extraction of the alkaloid fraction from Atropa belladonna root drug.

180 g of finely ground (particle size 160-320 μm) root drug were introduced into a cylindrical extraction vessel with a volume of 307.5 ml (26 x 547 mm) and compressed using nitrogen at 0.2 MPa gauge pressure. The upper and lower outlet of the cylindrical extraction vessel was provided with a glass filter with a pore size of 10 μm. The solid-liquid extraction was carried out continuously under pressure with chloroform saturated with aqueous ammonia. The solvent rate was 10 ml / min and the pressure was periodically adjusted as follows: 0.18 MPa overpressure, reduction to 0.03 MPa overpressure and maintenance of the lower value for 4 minutes. This periodic pressure change was carried out in accordance with Example 2. The extraction cycle was repeated 23 times. The effectiveness of the extraction was monitored by means of thin-layer chromatography (L. Botz, L. Gy. Szabo: J. Planar Chromatogr. JL (1988) 85). The extraction was found to be 92.6% effective.

The pressure profile, which preferably changes periodically during the extraction process according to the invention, is shown in FIG. 5. In this representation, p is the ambient pressure, p _{1 is} the lower pressure and p _? denotes the upper limit of the overpressure during the extraction. ΔT denotes periods of the highest pressure p_ during which the solvent flows quickly through the material to be extracted. A solution / diffusion process takes place. During the periods of low overpressure p denoted by Δt. the solvent is stationary, with a concentration equalization between the solvent and the material to be extracted.

The method is preferably controlled such that the length of the periods .DELTA.T for the solution / diffusion decreases to a value .DELTA.T ₃ = .DELTA.T ₄ , the periods .DELTA.t for the concentration compensation are increasing.

Claims

- 18 patent claims

1. A process for the exhaustive extraction of ingredients from finely divided solids arranged in a layer, characterized in that a solvent is forced through the layer of the finely divided solid by means of force.

2. The method according to claim 1, characterized in that m.an organic substances extracted from the finely divided solid.

3. The method according to claim 1 or 2, characterized gekennzeich¬ net that a biologic matrix, in particular finely ground plants or parts of plants, extracted.

4. The method according to any one of the preceding claims, characterized in that finely divided solids with a particle spectrum, as can be obtained by grinding, in particular with a lower particle size of 50 μm, are extracted.

5. The method according to any one of the preceding claims, characterized in that a finely divided solid mixed with a solid which is inert for the extraction is extracted.

6. The method according to any one of the preceding claims, characterized in that a mixture of substances is extracted from the finely divided solid.

7. The method according to any one of the preceding claims, characterized in that the strength of force used is varied during the extraction, in particular alternating periodically between periods with stronger and weaker force application or with and without force application.

8. The method according to claim 7, characterized in that periods of higher overpressure (Δ T) are varied with periods of lower overpressure (Δt), the duration of the periods of higher overpressure decreasing and that of the lower overpressure increasing.

9. The method according to any one of the preceding claims, characterized in that one extracts in succession with various solvents or solvent mixtures and the solid to be extracted is dried after each solvent or mixture by passing an inert gas through it.

10. Continuous process for extracting contents from finely divided solids according to one of the preceding claims, characterized in that the solvent is distilled off from the extract obtained and the solvent recovered is fed to the extraction again.

11. Continuous process according to claim 10, characterized in that the extract obtained after the extraction is subjected to one or more chromatography step (s), the solvent is recovered by distillation and the extraction is carried out again.

12. Continuous process according to one of the preceding claims, characterized in that the solvent is forced by means of excess pressure through a plurality of successively arranged layers of the finely divided solid.

13. Device for performing the method according to one of the preceding claims with an extraction vessel (22) for receiving the layer of the fine solid to be extracted (23), characterized in that the extraction vessel (22) on the inlet side with a pump (27) is connected to a reservoir (29) for solvent and has a shut-off device (35) on the outlet side, the pump (27) having a timer for switching the pump (27) on and off according to a predetermined time program and the shut-off device (35 ) a pressure regulator (26) for closing and opening the shut-off element as a function of the solvent pressure are assigned.

14. Device for carrying out the continuous method according to one of claims 10 to 12 with an extraction vessel (22) for receiving the layer of the fine solid to be extracted (23), characterized in that the extraction vessel (22) on the inlet side via a pump (27) communicates with a first storage vessel (29) for solvent and on the outlet side with a vessel (33) for the extract, the vessel (33) for the extract via a line (36) provided with a shut-off device (45) a vacuum distillation system (37) and the latter is connected via a further line (43) provided with a shut-off element (46) to the first storage vessel (29) for solvents, the shut-off elements (45, 46) being assigned at least one control element (26) which control the shut-off elements as a function of the liquid level in the two vessels (29, 33).

15. The apparatus according to claim 14, characterized in that the first reservoir (29) is connected to a second reservoir (47) for solvents.

16. The apparatus of claim 14 or 15, characterized gekenn¬ characterized in that one or more chromatography column (s) are arranged after the outlet opening of the extraction vessel.

17. Device according to one of claims 14 to 16, characterized in that all of its parts coming into contact with the solid to be extracted and the extract consist of an inert material, preferably glass and polytetrafluoroethylene.