PROCEDURE AND DEVICE FOR THE AGGLOMERATION OF SUSCEPTIBLE SUBSTANCES OF HYDROLYSIS THROUGH WATER VAPOR
FIELD OF THE INVENTION The invention relates to a special process for the agglomeration of substances that are difficult to dissolve and susceptible to hydrolysis, especially of pharmaceutical active substances coo, for example, acetylsalicylic acid (AAS), by the use of water vapor. The invention also relates to a device for carrying out the method. BACKGROUND OF THE INVENTION Many substances in a pulverulent state are poorly dispersed in liquids and, therefore, it is difficult - often their use for dispersions or solutions. In addition, a good flow behavior and a fine powder content as small as possible are often desired. This also applies to poorly soluble powders which can have both hydrophilic and hydrophobic surface properties. If the powders are used for galenic preparations, it is often also very desirable or necessary to achieve improvements or masking of the taste or to avoid or to minimize contact with other incompatible components of the mixture. The improvement of the humidification, the fluidity and the reduction of the fine powder content in the use of powders are usually achieved by the granulation REF: 24395 of the respective powder by means of a structural agglomeration process. Structural agglomeration processes are characterized by the use of granulation liquids, usually water or aqueous solutions. These processes are therefore not applicable for the processing of substances susceptible to hydrolysis, since with them there is generally a decomposition of the substance (active) with the formation of undesirable degradation products (pharmaceutically). If, therefore, non-aqueous organic solvents are used, this leads to residual solvent contents in the granules, which are also undesirable or inadmissible. By working with solvents, a higher cost for processing also results. It has been demonstrated that easily dispersible granules are obtained if, by the agglomeration process, very small bridges of solid matter are produced between the primary particles which, in redispersion in a liquid, can easily dissolve in it and are preferably composed of a material that is very soluble in the liquid. For a good dispersibility of the granulate, it is furthermore advantageous that compacting forces are avoided during the agglomeration, that is, in the still wet state of the granulate, since otherwise the contact sites between the wetted particles will be enlarged and bridges will be generated. Stable larger solid matter. DESCRIPTION OF THE INVENTION The object of the invention is a method for the agglomeration of substances susceptible to hydrolysis, especially of ASA, characterized in that the AAS powder hardly soluble together with at least one powdery binder easily soluble in water, is conducted in free fall through a water vapor atmosphere at temperatures between 852C and 105SC, preferably at about 1002C, essentially without the use of compacting forces, with a residence time in the vapor zone of about 0.5 to 10 seconds, preferably 1 to 3 seconds and then dried in another free fall, so that from the liquid bridges caused by the condensation at the contact sites between the particles of the water-insoluble active substance and the water-soluble binder, in which the binder is dissolved, small bridges of solid matter are produced and in a drying process immediately after In an integrated fluidized bed, it is dried to a water content of less than 5% by weight, preferably less than 1% by weight. As "small bridges of solid matter" it is understood here that the bridges of solid matter must have a medium transverse size (diameter or thickness) of 1 μm to 30 μm, preferably from 5 to 15 μm. Because the contact time of the water with the powder susceptible to hydrolysis is very short and also because the thermal load of the solid particles, with a maximum of 100 ° C, preferably a maximum of 86 ° C, is small and only acts during a very short time, essentially no degradation reactions occur during the process according to the invention. The dissolution of the particle surface of the binding agent by the condensed water vapor is carried out very quickly, the solutions originated therewith form at the contact points between the liquid bridging particles or they coat the particle-difficult to soluble susceptible to water. hydrolysis. The immediate evaporation of the water that takes place after the agglomeration, with formation of bridges of solid matter or (partial) coatings of the insoluble particles of active substance with the water-soluble auxiliary substances, guarantee the stability even of substances susceptible to hydrolysis , like AAS.
With the method described it is also possible, by choosing suitable ratios of active substance to auxiliary agent and favorable conditions of the process, a kind of microencapsulation or a coating of the insoluble substance in water. For the agglomeration or microencapsulation (partial) of the substances which are difficult to dissolve or insoluble, suitable water binding agents are used, such as polyvinylpyrrolidone (PVP), PVP derivatives, starch, starch and cellulose derivatives, sugar, sugar alcohols such as sorbitol. , xylitol, sugar derivatives such as maltodextrins, isomaltose, fruit acids and their water soluble salts such as citrates or tartrates, ascorbic acid, amino acids or also inorganic salts such as sodium sulfate. The weight ratio of the hardly soluble substance to the water-soluble binder-adjuvants amounts to 1 to 10 to 10 to 1, preferably
3 to 8 to 7 to 2. The mixture to be agglomerated, of substance - insoluble active susceptible of hydrolysis and water-soluble coadjuvant substance, is advantageously introduced from the top, together with water vapor, into the apparatus, spatially close together. The vapor condenses on the colder dust particles, the condensate film dissolves the binder, and the liquid bridges formed at the contact sites between the wetted particles are dried to give bridges of solid substance. In the case of a large excess of water-soluble auxiliary substances, a complete coverage of the active substance susceptible to hydrolysis can be achieved by the water-soluble coadjuvant. The process can also be applied in such a way that an active substance which is very soluble in water acts as a binder. An essential element of the process according to the invention is the use of an almost pure vapor atmosphere for direct wetting of the surface of the particles. However, with the simultaneous presence of air they should migrate by diffusion from the vapor to the surface of the particle the corresponding air pockets. Due to this, less vapor can condense on the solid substance, thus reaching a degree of agglomeration or coverage of the smallest active substance. Therefore, the purpose of the treatment of the powder capable of hydrolysis may not be satisfied or only insufficiently. For the execution of the method according to the invention, a device consisting of an agglomerator with a closed housing has been successful, at the upper end of which is arranged a dosing device for a powdery substance bound to a hopper, by which it originates in the agglomerator a veil of product of the powdery substance that falls freely. In addition, the device is equipped in the upper part of the agglomerator with nozzles for the production of steam jets which wrap, at least partially, within a vapor zone the product veil that falls freely. The characteristic according to the invention of this installation consists in that in the lower part of the agglomerator there is a fluidized bed dryer coupled next, in such a way that the agglomerated particles fall directly into the fluidized bed. Therefore, the fluidized bed dryer is integrated directly into the steam jet agglomeration system. The nozzles for the steam jets advantageously consist of tubes or orifices which are connected to a distributor tube extending in the longitudinal direction of the agglomerator, with distributing tubes being disposed towards each of the two faces of the product web. An essential element of the device according to the invention is also the separation of the vapor zone (wetting zone) from the drying zone. This separation is carried out according to a variant of the invention, having a double-walled protective tube in the upper part of the agglomerator., heated, enclosing the steam jet nozzles, through which cover the air to be evacuated is extracted. In this way, all the gaseous streams introduced into the installation through the fluidized bed drier can be removed through the lower closure of this protective tube. As an alternative, the separation of the steam zone from the drying zone can also be carried out by arranging, in the housing of the agglomerator, at a distance of 50 mm to 300 mm from the lower end of the steam jet nozzles-distribution pipes, a annular gap with a collector channel for the extraction of the air to be evacuated. In this way, all the air to be evacuated in the area between the wetting and drying parts can also be removed regularly, through the whole contour of the installation. A preferred variant of the device according to the invention is that the fluidized bed drier integrated in the steam jet agglomerator exhibits an outer annular fluidizing bottom which rises with a conical profile and a central inner fluidizing bottom, the speed of the current being of the fluidizing air coming out from the inner bottom greater than the velocity of the flow of the fluidizing air coming out from the outer bottom. Advantageously, a conical widening for the housing of the agglomerator is coupled to the conical external fluidizing bottom. These measures cause a circulating movement of the bed and prevent undesirable local over-wetting. The desired final moisture can be adjusted by a suitable residence time in the drying zone and / or the respective choice of the quantity and temperature of the drying air in the fluidized bed. The temperature in the fluidized bed is, accordingly, between 20 ° C and 70 ° C. With the invention, the following advantages are achieved: With the process, due to the small agglomeration humidity, temperature loading and, above all, the very short loading time, products susceptible to hydrolysis can also be successfully processed by wet agglomeration. In susceptible products, there is no degradation reaction or only a minimal degree. With the process according to the invention, agglomerates of size in the range between 200 and 3,000 μm, preferably between 200 and 2,000 μ can be obtained. - The agglomerates obtained with the process are "extremely well dispersible." Also for cold water redispersion, only very short times are required (usually less than 1 minute, preferably <; 30 seconds), which can only be achieved with redispersion in hot water with the usual agglomeration processes for granules (agglomeration in a mixer, fluidized bed agglomeration). - For bad tasting products, in the processing with flavoring products and / or aromas a good masking of the flavor is achieved. With the choice of suitable conditions for the process (especially with a sufficiently high binder fraction) it is possible not only to agglomerate insoluble products, but also to partially coat them. With this the surface of the insoluble particle is coated with the dissolved binder insofar as the binder solutions are capable of spreading over the insoluble product. In this case, coating from 40 to 80% of the surface, preferred from 50 to 70%, can be achieved. This has the advantage that the products thus coated exhibit a decreased reactivity to other components of the mixture. Therefore, mixtures of substances which normally exhibit a decreased storage stability can also be obtained. The very good solubility of the agglomerate is based on the fact that the bridges between the particles to be agglomerated (insoluble) are composed of a very soluble material of the binder that dissolves in fractions of a second in the condensed vapor!) Which is also very well wetted by water . The bridges between the particles, moreover, have a thickness of only a few μm (from 1 to 30 μm, preferred from 5 to 15 μm) and are concentrated at the site of contact between the particles. Therefore, a large surface is offered for a dissolution process. In the following, the invention is further clarified by virtue of exemplary embodiments and illustrations. Shows:
Figure 1: Schematically, the installation of agglomeration by steam jet with integrated fluidized bed dryer. Figure 2: A plan view of the steam jet nozzles with the distributor tubes. Figure 3: The protective tube for the functional separation of wetting and drying of the product veil that falls from above. Figure 4: An enlarged representation of the integrated fluidized bed dryer. According to FIG. 1, the steam jet agglomerator 1 and the fluidized bed dryer 2 are arranged vertically one above the other and enclosed in the same housing 3. The agglomerated product 4 leaving the agglomerator by steam jet 1 drops immediately to the fluidized bed dryer 2. The steam feed is effected through two steam jet nozzles 5 and 6 coupled in parallel, which are arranged facing the two faces of the product veil that falls from above. These are supplied through a common steam duct 7. The steam jet nozzles 5, 6 are also incunable around the angle. As shown in Figure 2, the steam jet nozzles 5, 6 consist respectively of a plurality of short tubes 8 or openings, which are attached to a distributor tube 9 which extends along the agglomerator. The cross section of the distributor tubes 9 decreases along them so that the tubes of the nozzle 8 are impacted by the same mass vapor flows. The length of the tubes of the nozzle 8 amounts to at least three times its diameter. The distribution tubes 9 and with them also the tubes of the nozzle 8 are incunable around the center of rotation 10, so that the angle under which the vapor is present on the product web is adjustable. The product veil flowing from the steam nozzles 5, 6, is impacted by the -vapor within a vapor action section d, whose length is determined essentially by the vapor exit velocity and the inclination angle a. This vapor action section is hereinafter referred to as the "vapor zone". The angle a is adjustable between a and 602. The optimum values are between 202 and 402. The solids feed is carried out through an endless screw feeder 11 to an elongated hopper 12, from whose lower end a regular veil of product emerges. pulverulent, homogeneous, through a groove and penetrates the part of agglomeration 1. In this way the particles approach each other but no compacting force appears. The region above the solids feed is likewise closed by a separate lid 13, so that an undesired penetration of air is prevented through the feeding of products, or only a controllable amount of air enters the installation. Too much unduly penetrated air would lead to an alteration of the vapor atmosphere and to the worsening of the binding action. The product to be agglomerated and the binder feed the screw feeder 11 in the form of a mixture. The product can be conditioned in the tank by a heater or a refrigerant, for example by air conditioning. The temperature of the product, that is, the temperature of the powder mixture in the screw feeder is a parameter of the adjustable procedure, which influences the amount of condensed steam and, therefore, directly on the result of the agglomeration (size of the agglomerate, humidity of the agglomerate). An important assumption for the attainment of reproducible conditions of the process and, therefore, of constant product qualities is the spatial separation of the wetting and drying zones, so that in the humidification an almost pure vapor atmosphere is guaranteed. For this purpose, in the housing 1, at the height of the site where the steam zone ends and the drying zone begins, an annular slit 14 is engaged., which is connected to a collecting conduit 15. Through this annular gap all the air to be evacuated is extracted from the fluidized bed dryer 2. In practice, the annular slit 14 is at a distance of 50 mm to 300 mm below the lower edge of the distributor tubes 9. An alternative possibility for the spatial separation of the wetting and drying areas is based on a protective cylinder surrounding the vapor zone (see figure 3). The protective cylinder 16 arranged concentrically to the housing 1 in the lid 13 is executed with a double wall. In this double jacket hot air is blown from below through a circular groove 17 in an annular tube 18 to heat the protective cylinder 16 and prevent steam from condensing on its walls. In addition, the annular tube 18 is coupled to the protective cylinder 16 in such a way that between the double jacket and the annular tube 18 an annular gap 19 remains. Because of the injector action of the hot blown air blown through this opening of the edge lower of the double jacket air is sucked from the interior space (arrow 20) so that a regular extraction of the air to be evacuated from the dryer throughout the entire contour is guaranteed. The hot driving air feeds the annular tube 18 through the air connections 21. The air to be evacuated is extracted from the double jacket through the air connections to be evacuated 22. In the steam zone, it is moistened by condensation the product veil and by this the agglomeration begins. After the humidification, the wet agglomerated product is precipitated, first by means of a reverse flow of drying, conditioned air from the fluidized-bed drier and, by this, pre-dried. The final drying to the desired final moisture is carried out in an integrated fluidized or swirl bed. By means of the height of the fluidized bed and by choosing suitable drying conditions (air temperature, amount of air) the desired residual moisture is achieved. The content of the fluidized bed is kept constant at a desired value with the help of a current filling regulator. Therefore, the moisture end of the product can be adjusted exactly independently of the humidity of the agglomerate reached in the vapor zone. The adjustment of the desired residual moisture is thus only made in all cases after the formation of the solid-substance bridges has been completed. The size and structure of the granulate depend on the recipe and the operating parameters chosen (ratio of solid quantities-steam, temperature of the solids, drying conditions). No recirculations of solids are necessary that can lead to the disintegration of the mixtures. According to FIG. 4, the fluidized bed in the dryer 2 is divided into several regions of different fluidization intensity (stream arrows 23 and 24). In the center, because of a separate central tube 25 with a perforated plate 26, the bed is fluidized more intensively than at the periphery, where the fluidization is effected in known manner by a perforated bottom 27 executed in an upwardly tapered shape. By this, the product that is still wet is immediately dispersed between the already dried product, thus preventing further granulation or agglomeration (sticking together of already agglomerated particles). It is thus avoided that the wet agglomerates that occur on the fluidized bed continue to agglomerate, sticking and leading to the collapse of the fluidized bed. Between the perforated bottom 26 ~ and the central tube 25 there is disposed an annular discharge groove 28 through which the dry final product corresponding to the content of the fluidized bed is extracted, that is, which corresponds to its average residence time in installation. This also ensures that no amount of product can leave the installation directly, that is, without the previous circulation through the fluidized bed. Directly above the perforated bottom 27 the installation widens. This conical widening 29 (towards the housing 1) supports the homogenous circulatory movement of the product and thus the distribution of the algomerate which is still wet, and favors the movement of particularly large particles towards the discharge 28. By means of the combined measures of the different fluidization achieved and the widening of the installation guarantee a particularly homogeneous circulation of the product. The installation of steam jet agglomeration with integrated fluidized bed, according to the invention, operates with the following process parameters and particle sizes of the products: Mass flows Vapor: 5 to 10 kg / h Solid: 10 to 100 kg / h Residence times Steam zone 0.5 to 3 s (preferred 0.5 to 1.5 s)
Fluidised bed 10 to 20 minutes Steam temperatures 1002C Fluidisation air 20 to 80 c Bed temperature 20 to 50ac Product 0 to 60ac Product particle sizes Particle size < 300 μm (preferred <200 μm) Binder content 5 to 90% Agglomerate: Maximum humidity (after the vapor zone) 4 to 5% approx. Final humidity (after drying in a fluidized bed) < 0.5% Agglomerate size 200 to 2,000 μm Exemplary embodiments Example 1 100 g of ASA powder are mixed with 50 g of xylitol as binder. The mixture, which has ambient temperature, is introduced into the agglomeration system by means of the auger 11, in such a way that an elongated, homogeneous veil of product is created. The mass flow of solids amounts to 20 kg. It is dosed at an angle a = 302C with 7 kg / h of saturated water vapor. The residence time in the steam zone and, therefore, the contact time with the steam amounts to i s. This results in granules of size comprised, preferably, between 150 and 1,000 μm. The granules have, just after leaving the humidification zone, humidity between 1.5% and 3% (determined with the aid of the Karl-Fischer titration method). The granules are then dried in the fluidized bed which is then coupled at bed temperatures of 400 ° C. to residual humidity below 1%. The residence time in the fluidized bed takes between 10 and 20 minutes. The granulate of AAS-xylitol thus obtained is very apt to the flow, has a good flavor and is redispersable to an outstanding degree. The content of undesired degradation products is below 0.5%. Example 2 100 g of ASA powder are mixed with 200 g of xylitol as binder. The mixture, which is at room temperature, is introduced into the agglomeration system by means of the auger 11 in such a way that an elongated, homogeneous veil of product results. The mass flow of products amounts to 30 kg / h. It is dosed at an angle = 4oac with 10 kg / h of water vapor (saturated). This results in granules of size comprised, preferably, between 150 and 1,000 μm. The granules have, just after leaving the humidification zone, humidities between 2.5% and 4% (titration according to Karl-Fischer). The granulates are dried in the fluidized bed which is then coupled to residual humidity below 1%. The thus obtained AAS-xylitol granulate has good fluence, has a good flavor and is redispersible to an outstanding degree. The content of undesired degradation products is below 0.5%. The surface of the AAS particles is coated by up to 50 to 70% with xylitol. In this way it is possible to mix and store the AAS together with other components with which it was not possible to date a joint mixture, for example with effervescent components or other basic components. EXAMPLE 3 100 g of AAS powder are mixed with 30 g of sucrose and 5 g of flavor, preheated to 50 ° C and introduced into the agglomeration system by means of the worm screw 11 in such a way that an elongated, homogeneous web is produced. of product. The mass flow of products amounts to 20 kg / h. It is dosed with an angle a of 30ßc with 6 kg / h of steam. Granules of size, preferably between 200 and 1400 μm, are produced. The granules have, just after leaving the wetting zone, humidity between 1 and 2.5% (titration according to Karl-Fischer). The granulates are dried in the fluidized bed which is then coupled to residual humidity below 0.5%. The granulate thus obtained has good fluence, has a good flavor and is redispersible to an outstanding degree. The content of undesired degradation products of the AAS is below 0.5%, the loss of usually volatile flavoring substances is below 10%. In this way it is possible to agglomerate AAS together with aromas. This offers the advantage that compared to the usual way of proceeding to mix aromas only for this purpose, a disintegration is avoided in the course of the subsequent processing, transport and storage, until the moment of application. EXAMPLE 4 100 g of AAS are mixed with 50 g of sodium sulphate and agglomerated by steam jet as described in example 1. After drying, this also produces a good yielding agglomerate, very quickly dispersible in water. , which can be used for formulations in envelopes or tablets. Example 5 500 g of paracetamol are mixed together with 100 g of citric acid, 400 g of orange flavor, 1,000 g of lemon flavor as well as 2,000 g of maltite as binder. The mixture is incorporated into the agglomeration system at room temperature by means of the auger 11, in such a way that an elongated, homogeneous product veil is created. The mass flow of solids amounts to 40 kg / h. It is dosed with an angle a of 20ac with 10 kg / h of water vapor. The residence time in the steam zone and, therefore, the contact time with the steam amounts to 1 s. This results in granules of a size comprised, preferably, between 200 and 2,000 μm. The granules have, just after leaving the humidification zone, humidities between 2% and 4%. The granules are then dried in the fluidized bed coupled below, at bed temperatures of 30 ° C, to residual humidity below 0.5%. The residence time in the fluidized bed takes between 15 and 20 minutes. The agglomerate thus obtained has good creep, has a good flavor and is redispersible to an outstanding degree. The quantitative ratio between the components after the agglomeration corresponds to that adjusted for the starting mixture, that is, no undesired disintegration occurs. The agglomerate can be used for formulations in sachets or as a tablet formulation. The agglomerate is dissolved in cold water (5 g in 100 ml) in a time of less than 15 seconds in an administrable beverage. It is noted that, with regard to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following: