DE10240778A1 - Process for the production of directly tablettable a-mannitol - Google Patents

Abstract

The present invention relates to a process for the production of directly tablettable mannitol with an alpha modification content of more than 90%.

Description

The present invention relates to a process for the production of directly tablettable mannitol with containing α-modification of more than 98% by weight.

Can be used to make tablets as a carrier material for one Active ingredient D-mannitol can be used. D-mannitol is usually used for this purpose Process steps with corresponding intermediate controls in one Powder or granule form transferred to it for to make the tablet presses manageable and at the same time one Enable drug integration.

Out US 3,145,146 A a spray drying process is known, whereby mannitol is obtained in the form of fine particles with an average diameter of 5 to 150 μm. A mannitol solution is spray dried by spraying in a hot gas stream. The particles obtained are separated off by suitable measures. A mixture of different crystal modifications is obtained by the process described.

For the production of powdered D-mannitol granulation in a fluidized bed is also known, in which the Process air flow a specially shaped inflow floor flows through creating a fluidized bed of solid starting material. The spray liquid passes through a nozzle system finely divided into the vertebral space. The swirling particles are wetted, the surface partially dissolved, and the particles stick together. At the end of the fluidized bed continuously removed solid. At the same time, at the entrance a smaller amount of solid is added to the spray liquid is distributed finely. A filter system ensures that no dust gets the fluidized bed leaves and only At the exit, granulate particles are removed that have a minimum size. Solid matter particles also form in such a fluidized bed, which are more or less statistically shaped. Corresponding plants are distributed by various manufacturers.

Usually includes a process step begins in the production of a powdery mannitol through which a powder with a uniform particle size distribution is obtained. This stage of the process can be both grinding and also include sieving (classifying) the powder. In the case the use of mannitol as a carrier material for pharmaceutical Active ingredients for the expert any additional Process step in manufacturing poses a possible danger of unwanted contaminants to be entered in the product.

It is also known from the literature that D-mannitol can exist in polymorphic crystal forms, these can be the α, β and δ form. The definitions and characterizations used here correspond who in: Walter Levy, L .; Acad. Sc. Paris, t. 267 Series C, 1779, (1968) given classification of the polymorphic forms by X-ray structure analysis (X-ray diffraction pattern). The β form is the most stable form, although conversions to the other forms dependent on of the storage time and the conditions of the environment are possible. In itself, it is therefore desirable for commercial Applications mannitol due to its stability in its beta form too preserved since the product properties are least affected in this case change by storage.

It is also known to be on the one hand for the tabletting properties of the powdered D-mannitol are important is in which polymorphic form it is and on the other hand in how the grain structure of the individual particles is built up is. This also has a decisive influence on the possibility Obtain tablets in which the active ingredients contained homogeneous are distributed.

WO 97/38960 A1 describes that improved tablet properties through a partial or complete conversion of the powdery D-mannits from the δ-form into the β form result. The conversion from the δ shape into the β form is caused by targeted wetting of the particle surfaces of the Powder with a water soluble solvent or water and by subsequent Dry. The percentage of β-mannitol formed depends on the amount of solvent used and the duration of the drying process. Usually is therefore in the product a mixture of δ- and β form available.

The disadvantage of this method is that the conversion is additional Process step connects to the actual powder production and the Drying requires at least 8 hours, with the system being continuous Thermal energy supplied must become.

In contrast to the described δ- and β-modification forms becomes α-mannitol so far mainly won from the melt. This process is labor and energy intensive. The product obtained in this way also has poor tableting properties.

Object of the present invention it is therefore an easy to do Process for the preparation of directly tablettable α-mannitol for disposal to deliver.

The object of the invention is also a procedure is available in a first step, by means of what can be directly tabletted Mannitol is produced, which in subsequent process steps in formulations containing active ingredient is incorporated and homogeneous and stable integration of the active ingredient in a simple manner in ß-mannitol is converted.

The task is therefore solved by a process for the production of directly tablettable α-mannitol containing more than α-modification than 90% by

• a) in a first step as an educt an aqueous D-mannitol solution, spray gas, powdered α-mannitol and hot gas are combined in a spray drying unit (B),
• b) the resulting powder Product falls into a fluidized or fluidized bed (A), taken up, fluidized and is transported on and
• c) a subset of the resulting powdered product in the process is returned and possibly
• d) in a special embodiment the resulting powder in one or more granulation step (s) with another liquid Sprayed medium, dried and in flowing or fluidized bed is transported further.

D-mannitol is used to prepare the mannitol solution with a purity of> 90%, preferably> 95% used. D-Mannitol with a purity is particularly preferred used by> 98%.

Surprisingly let yourself shift the balance towards the formation of α-mannitol by the α-mannitol as a dust component from the product discharge zone of the processor in step a) the Spray drying is returned. The method is particularly advantageous if α-mannitol is used an average particle size of less than 20 μm, in particular with average particle size in the range of about 1 to 20 μm, preferably in the range from 3 to 15 μm, is returned.

The return of the "dusty" α-mannitol, which comes from the powder dosing system in the line ( 9A ) is obtained as powdered α-mannitol by controlling the speed of the rotary valve 10A via the fan (E) into the spray drying (step a).

After balancing it is easily possible powdered α-mannitol with an average particle size smaller than 75 microns.

The special design of the used Facility enables it that the recycled powdered material before return by grinding in the fan (E), which also serves as a conveying device for the powder return, is crushed.

By regulating the speed of the rotary valve 10A and 10B of the system used and by grinding the coarse-grained (oversize) product in the fan (E) to particle sizes smaller than 75 μm before it is returned to the spray drying, only α-mannitol is formed.

To carry out the process, an aqueous, at least> 45% -ge, preferably> 50% ge D-mannitol solution used as starting material and with a temperature in the range of 60 sprayed up to 100 ° C.

Air or an inert gas selected from the group consisting of N ₂ and CO ₂ can be used both as the spray gas and as the carrier and heating gas. In the process according to the invention, the gas is preferably circulated and the circulated gas is freed of particles by filters, dried in the condenser and fed or heated again to the spray nozzles and introduced into the fluidized bed.

Preferably, the gas circulated freed of particles with the help of dynamic filters.

In a special embodiment of the method, the liquid media used have different Set up the system different compositions.

By varying the process parameters, spray pressure, Spray rate, Mannitol concentration, returned powder quantity, Hot air stream and temperature of the hot air can be in the inventive method targeted particle sizes between 50 to 1000 μm produce.

For this purpose, according to the invention, the air supplied to the system is preheated to a temperature in the range of 45-110 ° C. and the amount of supply air supplied is regulated in the range of 1000-2000 m ³ / m ² per hour, as a result of which the exhaust air temperature is in the range of over 40 ° C. At the same time, the spray pressure of the two-component nozzles is set in the range of 2-4 bar, so that approximately 1.5 to 3 m ³ / (h kg of solution) hot gas are fed to the two-component nozzle, the temperature of the hot gas being in the range of approximately 80 to 110 ° C. is set. Good process results are obtained if the powder recycling is regulated in such a way that recycling takes place in an amount in the range from 0.5 to 2.0 kg of solid / (h kg of solution).

A particularly uniform formation of pulverulent with an α-mannitol content> 95% takes place by setting the parameters, spray pressure, liquid quantity, mannitol concentration, returned powder quantity, hot air flow and temperature of the hot air, thereby reducing the powder quantity in the fluidized or fluidized bed to a bed quantity in the range from 50 - 150 kg / m ² bed is set.

A method for the production of pure α- (D) mannitol was found through experiments, by means of which directly tablettable mannitol (DC mannitol) with a suitable homogeneous particle size distribution can be produced. Mannitol with a purity of over 98% is used to carry out the process, the rest being sorbitol and other residual sugar. An aqueous solution with a mannitol content of at least 45% by weight is produced. This solution is sprayed and dried with a supply air temperature of approx. 60 - 110 ° C in a spray drying system. An aqueous solution with a mannitol content of more than 50% by weight is preferably used for this process step. Experiments have shown that it is also possible to use solutions with more than 60% by weight of mannitol under suitable conditions and products with an α-mannitol content of> 95% are obtained.

To carry out the method, a procedure as described in DE 1 99 27 537 described system used, but was slightly changed. With the system described in this patent application, it is per se possible to vary the properties of spray-dried or granulated, powdery products with respect to grain size, grain size distribution, moisture and tabletting ability. However, the changes to the system enable additional fine adjustment through the powder return.

In particular, the method is carried out in a spray drying plant, Which

• a) a spray drying unit (B)
• b) a fluid bed (A)
• c) one or more additional spray or atomizing nozzles for liquid media (C)
• d) a powder dosing device (D) and
• e) a powder return ( 9 ) with fan (E), the lines provided for powder recycling ( 9A ) and (9B) with rotary locks ( 10A . 10B ) are provided and the powder not entering the powder metering ( 8th ) can be separated into a dust-like and a coarse-grained fraction.

In the spray drying unit (B) of the system used according to the invention, liquid medium ( 5 ), Spray gas ( 6 ), powdery material ( 9 ) and hot gas ( 4 ) merged.

A special embodiment is that in a spray tower a spray drying unit (B) vertically over a subsequent one horizontal fluidized bed.

In a special embodiment the spray drying unit (B) the plant a spray system included that from a hot water heated dual-substance spray nozzle with coaxial arranged powder return and Flow of hot gas exists.

In the system used, one or more additional spray or atomizing nozzles for liquid media (C) can also be attached locally in the fluidized bed. The fluid bed is followed by a powder metering system (D) separated by a lock flap (F), which is separated by a product overflow ( 8th ) is fed. A portion of the product formed can be transported by flight, in which a fan (E) serves as a conveying device, if necessary after comminution ( 9A . 10A ) or uncrushed ( 9B . 10B ) are returned to the spray drying unit (B). The fan (E), which acts as a conveying element, can simultaneously serve as a shredding unit for the recycled powder.

Implementation of the manufacturing process of spray dried powdery α- (D) mannitol done by

• a) in a first step, a liquid medium, spray gas, powdery material and hot air are brought together,
• b) the existing powder Product in a fluid bed falls is absorbed, fluidized and transported and if necessary
• c) in one or more granulation step (s) with further liquid Sprayed medium, dried
• d) and in the fluid bed is promoted in the direction of the powder dosing system, from which
• e) a subset of unground and / or ground as a powdery material is returned to the process.

The liquid medium is preferably for a solution. But it can also be a watery one Suspension of already formed α- (D) mannitol, however must be sprayed immediately after their production, since α- (D) mannitol in Presence of water is unstable and rearranges into the β-form.

A special variant of the process is that recycled powdery material crushed before return can be.

Air or an inert gas selected from the group consisting of N ₂ and CO ₂ can be used as the spray, carrier and heating gas. According to the invention, the gas can be circulated, whereby it is freed of particles by filters or especially with the aid of dynamic filters, dried in the condenser and fed or heated again to the spray nozzles and introduced into the fluidized bed.

To carry out the process, the system is started with powdered starter material via the filler neck ( 3 ) loaded. About the chambers ( 1 ) an air flow is generated in the spray drying room. The introduced starter material is fluidized by this air flow and moves in the direction of the discharge flaps (F). The powder flow receives this direction of movement when the air flow is generated by appropriate perforation of the Conidur floor. The fluidized product can be discharged by simply opening the lock flaps (F). At this point in the system, devices have been created which make it possible to either return the product to a powder metering system or to the spray drying unit via a flight conveyor. There is an overflow at the discharge via the powder dosing system ( 8th ) for the finished product. The fan (E) of the spray drying unit serves both as a conveying means for the product and as a comminution unit for powder material to be returned. Returned powder material from the return line ( 9A . 9B ) due to the special design of the spray drying nozzle with the appropriate media, liquid ( 5 ), Spray air ( 6 ) and hot air ( 4 ) merged. The corresponding powder or granulate is taken up by the fluid bed and, as already described above ben, transported on. When passing through the granulation nozzles (C), further medium, which may have a different composition than that introduced into the spray nozzle with powder return, can be sprayed onto the particles formed. In this way, further granulation and readjustment of the grain size distribution can take place. The product from the chambers ( 1 ) is dried to the desired final moisture by air which is introduced through the conidur floors. The dynamic filter (G) integrated in the system prevents powder particles from being discharged into the environment.

Instead of the granulation nozzles (C), as in 1 shown, one or more spray nozzles or spray drying nozzles or only one, two or more than three granulation nozzles can be attached to the corresponding point of the system. These additional nozzles can be located directly at the beginning of the fluid bed or moved further back. The choice of the location at which the powder material originally formed is sprayed again once or several times depends, among other things, on the residual moisture content of the desired product. It goes without saying that a product with a particularly low residual moisture after the last spraying requires a longer residence time in the fluidized bed than one with a higher one.

Depending on your wishes, you can go through the different Nozzles different Compositions applied to the particle surfaces already formed be so that particles with a layered Structure can be obtained. However, it can also be used to achieve a more uniform grain distribution.

Furthermore, the system can not only with air as the carrier medium operate. It is also possible, the entire system in a circuit with an inert gas, e.g. nitrogen or carbon dioxide to drive.

The system is designed so that the parameters Amount of liquid spray pressure, returned powder quantity, Quantity of hot gas, Hot gas temperature, amount of hot air, Warm air temperature, etc. are individually adjustable. Therefore leave the amount of powder returned, the amount of liquid fed in and the spray pressure selectively set according to the desired Properties with regard to moisture, grain size and Particle size distribution of the end product. Depending on your wishes, you can use the system described powdery Products are manufactured with particle sizes between 50 and 1000μm. Depending on Driving style and chosen Process parameters can the particles have a layered shape (Bulb structure) structure or depending on an agglomerate structure.

The formation of the particles can be particularly controlled by a spray nozzle integrated in the system, which is suitable for producing spray-dried granules. This spray nozzle is a spray system (B) which consists of a two-substance spray nozzle that can be heated with hot water [( 1 ), ( 2 ), ( 3 )], which in turn has a powder return arranged around the two-substance spray nozzle ( 4 ) and a hot gas flow ( 5 ) Is provided. In special cases, powder recycling ( 4 ) be arranged coaxially around the two-component spray nozzle.

Advantage of this spray system is that recycled powder directly at the outlet of the two-component spray nozzle with those generated via the atomizing air Droplets of liquid in Contact comes. So that the powder particles do not stick together and the surface moisture dissipated can be sprayed and powder part of the spray nozzle with powder return in a hot gas flow locked in. The drying to the desired residual moisture takes place in the fluidized bed instead of.

Especially through the installation this spray drying system Is it possible, to produce specific particle sizes.

A particular advantage of this spray drying process therefore consists in the fact that in a single plant without further Process steps for post-treatment of the product depending on the set process parameters and the used ones sprayed liquid Media powdered α- (D) mannitol with very different properties in terms of moisture, the Grain size, the Particle size distribution, bulk density and can produce grain structure.

For particularly good DC properties (DC = directly tablettable) of the spray-dried material, here α- (D) mannitol, it is beneficial in spray drying to agglomerate formed individual particles. For this purpose perpendicular to the Fluidized bed a spray tower over the spray drying unit according to the invention (B). In the variant of the possible system structure shown, this is Fluid or fluid bed constructed horizontally, where the product by the set airflow is transported to the exit.

The hot aqueous mannitol solution is passed through one or more two-component nozzle (s) ( 5 ) ( 6 ) with hot water ( 7 ) is (are) heated, sprayed. The spray jet generated is from a mannitol powder return arranged around this nozzle ( 9 ) and hot gas ( 4 ) flows around. The solid crystallizes in the spray jet, forms agglomerates and is collected by the fluid bed. The fluidized bed is filled with hot air from the air intake chambers ( 1 ) flows through and fluidized. The bottom of the fluidized bed is designed as a Conidur floor, which ensures the targeted transport of the solids to the discharge. With the help of the Conidur floor, a defined residence time of the solid in the fluidized bed can be set. The dwell time of the product in the processor can also be controlled by the bed height, spray and return quantity. The solid was introduced through several air inlets connected in series mern ( 1 ) transported and dried to a residual moisture <0.3%. The drying process takes place over the length of the fluidized bed in a certain temperature profile to avoid overheating of the product.

The vortex air, which is laden with water and contains dust, is cleaned via dynamic filters (G) and through the exhaust air chambers ( 2 ) dissipated. The dynamic filters are cleaned regularly with blows of compressed air. The cleaned dust binds the spray mist out of the spray zone and prevents caking on the walls.

The dried solid falls through double pendulum flaps (F) or other discharge systems into a dosing system of the return (D). The discharged product can optionally be further processed using a classification system. The oversize (and undersize) can be removed via the powder return ( 9 ) ground in the fan (E) and returned to the spray dryer together with the undersize (dust-like mannitol powder with particle sizes smaller than 75 μm, in particular smaller than 40 μm).

A partial flow is discharged as a finished product ( 8th ) removed. The product can be classified using a sieve, the oversize (remanence or coarse-grained powder fraction) via the suction side of the grinding fan ( 9A ) can be returned, ground and returned to the process. This minimizes product losses, among other things.

The fan (E) of the spray drying unit serves both as a means of conveying the product to be returned (solids feed on the pressure side ( 9B )) and as a shredding unit for recycled powder material (solids feed on the suction side (9A)). The two partial solids flows are determined, for example, by the speed of the rotary valve ( 10A . 10B ) controlled. Returned powder material of the return lines ( 9 ), as already described above, the special design of the spray drying nozzle with the appropriate media turns liquid (mannitol solution) ( 5 ), Spray air ( 6 ) and hot air ( 4 ) merged.

From the product discharge zone of the processor the supply air is fed to the fan (E). That way the fine dust (<15μm) is removed from the product at the same time (pneumatic classification). At the same time, the removal of this fine dust the effect that when using this product, which is freed from fine dust higher tablet hardness can be achieved.

With the partial flow 9B exists after the rotary valve 10B the option of sieving the oversize (remanence) from the return in order to better control the process. This oversize (remanence) can be added on the suction side to the grinding fan (E) or another comminution machine, ground and fed back into the process.

As already indicated above, the quality of the agglomerates and thus the product can be controlled via the system parameters such as concentration, spray pressure, temperature, spray quantity, powder return quantity, main air quantity, dust extraction, bed height etc. By reducing the height of the spray nozzle [(B) → (C)] above the fluid bed, it is possible to convert the grain structure from an agglomerate (berry structure) to a granulate (onion structure). With the lowest possible arrangement of the nozzles (granulation nozzles (C)), the powder return ( 9 ) over the filler neck ( 3 ) respectively. In order to continuously obtain a product that can be directly tabletted, the grain structures, but also modification, grain size distribution, water content, density, etc. must be monitored. It has been found that the best tablettable product is obtained when mannitol crystallizes out in a fine needle structure.

In 1 is a SEM photograph of a product with a proportion of α-modification of more than 98% in a 500-fold magnification.

Trials have shown that it is necessary to set the parameters of the spray drying process to observe and monitor to a constant, well tablettable, pure α-mannitol receive.

To prepare a formulation the DC becomes α-mannitol homogenized in a mixer with the active ingredient and can be used immediately be tabletted. You save yourself the intermediate steps of agglomeration or Granulation with subsequent Classification and drying. By adding water and through the dwell time one can convert the α-modification into the β modification Taxes. With some active ingredients, this conversion has the advantage that she be integrated into the grain structure of the mannitol.

According to the invention is preferably used as a starting material D-mannitol with a purity> 90%, particularly preferably with a purity of> 95% and very particularly preferably with a purity> 98%. This educt is used as an aqueous> 45% solution and sprayed into the system at a temperature in the range of 60 to 95 ° C. Preferably will be the solution before spraying heated to a temperature in the range from 70 to 95 ° C., in particular from 75 to 90 ° C.

According to the invention, solutions with different mannitol concentrations can be used at different points in the plant. It has proven to be useful to load spray nozzles above the fluidized bed in the direction of the product discharge with solutions with higher mannitol concentrations than spray nozzles that are located at the beginning of the fluidized bed. At the end of the fluidized bed, a solution with a mannitol concentration of about 60% by weight, based on the total solution, can therefore be used, whereas the Two-component nozzle with powder recycling is preferably operated with an at least 45% by weight aqueous solution. In this way, the product properties can be influenced again in the desired sense, whereby the system parameters must be carefully observed in this mode of operation.

By varying the parameters, spray pressure, amount of liquid, returned powder quantity, hot air flow and temperature of the hot air can be targeted particle sizes between Set 50 to 1000 μm.

Furthermore, it was found that the parameters of the system used according to the invention must be set as follows in order to obtain a constant product:
The spray pressure of the two-component nozzles should be set in the range from 2 to 4 bar, preferably in the range from 2.5 to 3.5 bar.

The amount of hot gas supplied to the two-gas nozzle must be regulated so that approximately 1.5 to 3 m ³ / (h kg of solution) are conveyed at a temperature of approximately 80 to 110 ° C. It was found that with a higher hot gas supply, a better product quality is obtained when working at a lower temperature.

According to the invention, the powder recycling is to be set in this way that a solids return in the area from 0.2 - 2.0 kg solid / (h kg solution) he follows. Preferably in the range of 0.5 to 1.5 kg of solid / (h kg solution) worked. Very cheap the process is designed when the solids return is in the range of 0.5 to 1.0 kg solid / (h kg solution) lies.

In order to carry out the procedure, the Plant preheated Air can be fed. Good results are achieved when the supplied to the system Air is preheated to a temperature in the range of 45-120 ° C. It is favorable for the process according to the invention when the supply air has a temperature in the range of 65 to 110 ° C. Especially beneficial for the formation of an α-mannitol powder with good tableting properties it is when the temperature of the fed air is in the range of 70 to 110 ° C.

The amount of supply air supplied is to be regulated according to the invention in such a way that 1000-2000 m ³ / m ² per hour, in particular 1200 to 1700 m ³ / m ² per hour, are fed into the system.

In connection with the other set parameters lie cheap Process conditions if the air flow in the system is guided in such a way that the exhaust air temperature is in the range of at least 40 ° C.

Furthermore, it has proven to be advantageous to regulate the process conditions in such a way that the amount of powder in the fluidized or fluidized bed adjusts to a bed amount of 50-150 kg / m ^{2 of} bed. It is particularly favorable if the bed quantity is in the range of 80-120 kg / m ^{2 of} bed.

It was also found that the process can be controlled, in particular by targeted recycling of a powder with a selected particle size.

As can be seen from the system diagram, can both a powder return by removing powder from the fluidized bed and by recycling one very fine-particle powder extraction, which is used in d. H. Homogenization of the particle size by sieving and filling the manufactured product respectively.

It is also possible to comminute powder with larger particle cross sections in the fan (E) of the spray drying unit beforehand. As already indicated above, the powder flow can be adjusted by adjusting the speed of the rotary valve ( 10A . 10B ) to be controlled. In order to grind powder to be recycled to the desired particle size in advance, the speed of the rotary valve is accordingly 10A (B) to be set so that the fan is fed back with grinding.

Trials have shown that Balance shifted towards the formation of α-mannitol can be if the average particle size of the recycled, in Fan (E) ground powder is less than 75 μm. In particular α-mannitol is preferably formed when the average particle size of the recycled powder is smaller than 40 μm is. Surprised was found that by returning a Powder with particle sizes smaller 20 μm mannitol powder with an a fraction of more than 90 is obtained. Particularly surprising it was found that in particular by recycling the so-called dust fraction, that occurs in the product discharge zone of the processor and usually is removed from the product to a uniform product with a special leads to a high proportion of α-fraction. The average particle size of the dust fraction is in the range from about 1 to 20 μm, in particular in the range from 3 to 15 μm. Moreover it was found that the dust from the return to a stable driving style in the spray zone of the processor.

Since these particle sizes can only be achieved with particular effort by grinding in the fan (E), the "dust-like" product portion from the powder metering system, which is in the line in the line ( 9A ) occurs by controlling the speed of the rotary valve 10A returned to the spray drying by grinding. By simultaneously throttling the speed of the rotary valve 10B a return of coarse-grained mannitol is reduced.

Surprisingly, it was found that in the process after the equilibrium was set in the direction of the formation of α-mannitol in a purity of more than 95%, the process can be continued in a stable manner, if the fan also did so a particle size of less than 75 μm ground powder is returned.

In this way it is surprisingly possible to start the spray drying process by returning only the "dust content" by regulating the speed of the rotary valve 10A and 10B set so that the only formation of α-mannitol takes place. Subsequently, the coarse-grained portion (the so-called oversize) of the mannitol powder formed can also be returned to the process without risking a shift in the equilibrium. This has the advantage that adherence of the particularly fine-particle spray mist to the walls of the system can be avoided in continuous operation, and disruptions to the process flow can be prevented.

By a suitable choice of the process parameters let yourself a product containing α-modification of more than 90%. By constant control of the manufactured Product quality can be the proportion can easily increase to a content of α-modification to over 95.

In particular with optimal setting of the system parameters described above and control of the other process parameters, a mannitol is obtained in the process according to the invention as a product with the following properties:
- Mannit directly tabletable
- Purity of the α modification> 95%
- bulk density 350 - 500 g / l
- residual moisture <0.3%
- Particle distribution: x ₅₀ at 200 μm: <10% <53μm + <15%> 500μm x ₅₀ at 300μm: <10% <100μm + <10%> 850μm x ₅₀ at 450μm: <5% <00μm + <10% > 850μm

Because the different modifications very similar to mannitol they are not usually due to their analytical nature differentiate measured melting temperatures in the DSC. The identification is exclusive e.g. possible with X-Ray or NIRS.

Because of the manufactured with the Product achieved tablet hardness however, there are clear differences to commercially available products. Compared to a commercial product, which has a relatively high proportion of α-modification in powdered mannitol has, with the α-mannitol tablets produced according to the invention with about 45 to 70% higher Get tablet hardness.

While The storage of DC α-mannitol must be done be made sure that the Atmosphere dry is. It is advantageous to store the DC α-mannitol in a WPK with a PE bag and integrated desiccant, because PE bags are not impermeable to water vapor. Moisture changes the α-modification of the Mannits in the ß modification around. Under the conditions described, however, it is stored for several years of the DC α-mannitol possible, whereby the α modification resistant is.

Trials have also shown that compared to the δ shape of mannitol is α-mannitol easily convert to the β-form by adding moisture leaves. For this purpose, water is added to by adding quantities and the dwell time in this process step is the conversion of the α-mannitol into that of β-mannitol to control. You have to make sure that the Mannite particles if the size is too large and faster addition of water can change.

For the homogeneous integration of active ingredients now in a first step after the production of the directly tablettable α-mannitol the active ingredient is introduced into a suitable mixer and homogenized with the α-mannitol.

To prepare a formulation the DC becomes α-mannitol homogenized in a mixer with the active ingredient and can be used immediately be tabletted. By adding water and by the dwell time can be used to control the conversion of the α modification into the β modification. This conversion has the advantage with some active ingredients that they are in the grain structure of the mannitol can be incorporated.

1 shows a generalized flow diagram of a possible embodiment of a spray drying system used to carry out the method, in which the given numbers and letters have the following meanings:

1

Air introduction chambers

2

heaters

3

filler pipe

4

Hot air supply

5

hydration

6

spray air

7

heating medium

8th

product

9

powder

( 9A fine powder (dust), 9B coarse-grained powder)

10

Rotary valve ( 10A and 10B ) to regulate the powder

return

A

Fluidized bed apparatus

B

Spray drying unit

C

granulation nozzles

D

Powder-metering

e

fan for powder recycling

F

sluice valves

G

dynamic filter

On the basis of the components mentioned in the description and given in the flow diagram, it is readily possible for the person skilled in the art to carry out the process by selecting individual components which are commercially available to create the appropriate system. It goes without saying for the person skilled in the art that additional electrical and mechanical control units must be installed to operate the system in order to be able to regulate and vary the parameters in the method according to the invention as described.

For a better understanding and clarification of the invention, a general flow diagram ( 1 ) of the spray drying system described and examples given for the production of the directly tablettable α-mannitol as well as for exemplary formulations in which the active ingredient is bound in the mannitol by converting the α-modification into the β-form. Both the examples and the flow diagram are not suitable for restricting the scope of protection of the present application only to these, since it is readily possible for a person skilled in the art to carry out a wide variety of variations in the structure of the system and to replace individual parts of the system with devices having the same effect. It is also easily possible for him to carry out the given examples in a suitable manner in a modified form and also to come to the desired result.

Examples

example 1

Production of a DC α-mannitol with an average grain X ₅₀ = 200 μm

In preparation, the spray drying system is filled with approx. 70 kg / m ² a-mannitol as a bed. (This bed should have the desired product properties if possible. If the bed material available has other properties, you have to start up the system gently until the balance has shifted in the desired direction.)

The system is operated as swirl and supply air at 1200 m ³ / m ² h at a temperature of over 90 ° C. (Before starting up the system, make sure that there is sufficient dust in the system. It can be done via the powder dosage (D), the suction-side return ( 9A ) and dosage ( 10A ) Dust is generated via / with the fan (E) and blown into the system.) If there is enough dust in the system, the dosage ( 10A ) of the recycle are reduced and the spraying of mannitol solution is started. The sprayed solution has a concentration of approx. 45% and a temperature of approx. 75 ° C. At a spray pressure of approx. 3 bar (spray medium is air), approx. 45 kg / m ² h of solution are sprayed in the system. About 0.5 kg of solid / (h kg of solution} are added via the powder metering (D) via the return ( 9 . 10 ) returned to the spray zone. The tent bikes ( 10A . 10B ) are regulated so that there is always a sufficient amount of product ( 9A . 10A ) ground in the fan (E) and with the unground product ( 9B . 10B ) is pumped back into the system.

The evaporation of the water in the system creates a balance with a bed temperature of over 45 ° C. The exhaust air temperature is over 35 ° C. (It is important to ensure that the exhaust air is as saturated as possible. This is advantageous both for the efficiency of the process and for the crystallization process of mannitol. In this way, the best crystal structure and the purest α-modification of mannitol are obtained Since the fan (E) draws its supply air from the product discharge zone in front of the sluice flaps (F) of the system (A), and thus the discharged product is dust-free due to the pneumatic classification, the product discharge ( 8th ) the α-mannitol with excellent properties for direct tableting. In order to obtain DC α-mannitol with the desired particle size distribution, it can be placed after the discharge lock (F), ie before the product discharge ( 8th } and the powder dosage (D). It is advantageous for the process to also remove oversize particles from the product to be recycled ( 9B . 10B ) to sieve, as this would otherwise accumulate further in the spray zone and can cause problems in the fluidized bed. The sieved undersize and oversize particles can be fed to the fan (E) on the suction side, ground, and together with the other recycled partial solids flows ( 9A . 10A . 9B . 10B ) are returned to the process. In this way, product losses are minimized and the process runs more stable thanks to the additional dust recycling (ground product).

Example 2

Production of a DC α-mannitol with an average grain X ₅₀ = 300 μm

As described in Example 1, the spray drying system is prepared and started up with about 100 kg / m ^{2 of} α-mannitol as a bed.

The system is operated as a vortex and supply air at 1500 m ³ / m ² h at a temperature of over 90 ° C. The mannitol solution to be sprayed has a concentration of approx. 50% at a temperature of approx. 80-90 ° C. At a spray pressure of approx. 3 bar (spray medium is air), a solution quantity of approx. 65 kg / m ² h sprayed in the system. The cellular wheels ( 10A . 10B ) are regulated so that a sufficient amount of product ( 9A . 10A ) ground in the fan (E) and with the unground product ( 9B . 10B ) is pumped back into the system. The evaporation of the water in the system creates a balance with a bed temperature of approx. 45 ° C. The exhaust air temperature is approx. 40-45 ° C. Make sure that the exhaust air is as saturated as possible. The oversize from the product to be returned ( 9B . 10B ) is screened out, otherwise it will continue to accumulate in the spray zone and cause problems in the fluidized bed. The sieved undersize and oversize particles are fed to the fan (E) on the suction side and ground. Together with the other recycled partial solids flows ( 9A . 10A . 9B . 10B ) fed back into the process.

Example 3

Production of a DC α-mannitol with an average grain X ₅₀ = 450 μm

As described in Example 1, the spray drying system is filled with about 120 kg / m ^{2 of} α-mannitol as a preparation. As a vortex and supply air, the system is operated at 1700 m ³ / m ² h at a temperature of approx. 100 ° C.

The hot gas is supplied to the spray zone in a range of approximately 1.6 m ³ / (h kg of solution) at a temperature of approximately 100 ° C. If these old parameters have been set, spraying of mannitol solution can begin.

The solution has a concentration of over 55% by weight at a temperature of approx. 90-100 ° C. At a spray pressure of approx. 3.5 bar (spray medium is air), a solution quantity of approx. 100 kg / m ² h is sprayed in the system. Via the powder dosing (D), the return ( 9 . 10 ) Bed / product of approx. 0.8 - 1.0 kg solids / (h kg solution) returned to the spray zone. The cellular wheels ( 10A . 10B ) are regulated so that there is always a sufficient amount of product ( 9A . 10A ) ground in the fan (E) and with the unground product ( 9B . 10B ) is pumped back into the system.

In the plant is formed by the Evaporation of the water equilibrates with a bed temperature from approx. 40-50 ° C. The exhaust air temperature is approx. 40-45 ° C. Make sure that the exhaust air is as saturated as possible.

The oversize from the product to be returned ( 9B . 10B ) is screened out, otherwise it will accumulate in the spray zone and cause problems in the fluidized bed. The sieved undersize and oversize particles are fed to the fan (E) on the suction side and ground. Together with the other recycled partial solids flows ( 9A . 10A / 9B . 10B ) added to the process again.

Claims (19)

A process for the preparation of directly compressible mannitol having a content of α modification of greater than 90%, characterized in that a) an aqueous D-mannitol solution, spray gas, pulverulent α-mannitol and hot gas are combined in a spray-drying unit (B) , air or an inert gas selected from the group consisting of N ₂ and CO _{2 being} used both as spray gas and as carrier and heating gas, b) the resulting powdery product falls into a fluidized or fluidized bed (A), is taken up, fluidized and transported on and c) a portion of the resulting powdery product is returned to the process and, if appropriate, d) the resulting powder is sprayed with further liquid medium in one or more granulation step (s), dried and transported further in the fluidized bed or fluidized bed (A) Method according to the claim 1, characterized in that the dust content in the product discharge zone α-mannitol in the processor the step a) of spray drying is returned and shifted the crystallization equilibrium towards the formation of α-mannitol becomes. Method according to claim 2 characterized in that α-mannitol with a average particle size smaller 20 μm, in particular with average particle size in the range of about 1 to 20 μm, preferably in the range from 3 to 15 μm, is returned. A method according to claims 2 and 3, characterized in that the "dusty" α-mannitol, which in the line ( 9A ) arises from the powder dosing system as powdery α-mannitol by controlling the speed of the rotary valve ( 10A ) is returned to the spray drying (step a)) via the fan (E). Method according to claim 1, characterized in that for the preparation of the mannitol solution used D-mannitol with a purity of> 90%, preferably> 95% is used. Method according to claim 1, characterized in that for the preparation of the mannitol solution used D-mannitol with a purity of> 98% is used. Procedure according to a or more of the claims 1 to 6, characterized in that after adjusting the balance powdered α-mannitol with an average particle size smaller than 75 μm is returned. Procedure according to a or more of the claims 1 to 4, characterized in that after adjusting the balance powdery unmilled α-mannitol is returned. Procedure according to (the) Expectations) 7 and / or 8, characterized in that the recycled powder material before return by grinding in the fan (E), which also serves as a conveying device for the powder return, is crushed. Method according to one or more of claims 1 to 9, characterized in that by regulating the speed of the rotary valve 10A and 10B and by grinding the resulting coarse-grained product in the ventilator (E) to particle sizes smaller than 75 μm, the only formation of α-mannitol takes place before being returned to the spray drying. Method according to claims 1 to 10, characterized in that an aqueous at least 45% D-mannitol solution as Educt is used and with a temperature in the range of 60 up to 100 ° C sprayed becomes. Method according to claim 1, characterized in that the Gas circulated is and the circulated Gas is freed from particles by filters, dried in the condenser and again fed to the spray nozzles or heated up and into the fluid bed introduced becomes. Method according to claim 12, characterized in that the gas using dynamic filters is freed of particles. Procedure according to a or more of the claims 1 - 13, characterized in that the liquid media used in different places of the plant have different compositions. Method according to claims 1 to 14, characterized in that by varying the parameters spray pressure, Spray rate, Mannitol concentration, returned powder quantity, Hot air stream and temperature of the hot air targeted particle sizes between 50 to 1000 μm getting produced. A method according to claim 15, characterized in that the air supplied to the system is preheated to a temperature in the range of 45-120 ° C and the amount of supplied air is supplied in the range of 1000 - 2000 m ³ / m ² per hour, whereby the Set the exhaust air temperature in the range above 40 ° C. A method according to claim 15, characterized in that the spray pressure of the two-component nozzles is set in the range of 2-4 bar and about 1.5 to 3 m ³ / (h kg of solution) hot gas at a temperature of about 80 to 110 ° C is fed to the two-component nozzle become. Method according to claim 15, characterized in that the powder recycling in an amount in the range from 0.2 - 2.0 kg solid / (h kg solution) he follows. A method according to claim 15, characterized in that by adjusting the parameters, spray pressure, amount of liquid, mannitol concentration, returned powder amount, hot air flow and temperature of the hot air, the amount of powder in the fluidized or fluidized bed to a bed amount in the range of 50-150 kg / m ² bed is set.