System and method for continuous processing of powder products - Patents.com

Abstract

The present invention relates to a system for continuously processing a powder product, the system comprising a first inlet for a first dry powder, a second inlet for a second dry powder, a powder mixing apparatus for continuously feeding a product mixture consisting of the first and second dry powders, the powder mixing apparatus having an outlet for the product mixture, and a manufacturing machine comprising a powder feed frame having a feed frame inlet connected to the powder mixing apparatus outlet, the feed frame inlet being lower than the feed frame inlet of the manufacturing machine, and a product conveying apparatus located at the junction between the powder mixing apparatus outlet and the feed frame inlet of the manufacturing machine, the product conveying apparatus continuously conveying the product mixture to the feed frame inlet of the manufacturing machine. The present invention also relates to a method for processing powder.

Description

[Technical field]

[0001] The present invention relates to a system for continuously processing powder products comprising a first inlet for a first dry powder product, a second inlet for a second dry powder product, and a dry powder mixing apparatus for continuously feeding a product mixture of the first and second dry powder products, the dry powder mixing apparatus having an inlet connected to the first inlet for the first dry powder product and the second inlet for the second dry powder product and an outlet for the product mixture, and further comprising a production machine comprising a powder feed frame having a feed frame inlet connected to the outlet of the dry powder mixing apparatus, and an outlet.

[0002] The invention further relates to a method for continuously processing a powder product, the method comprising the steps of continuously feeding a first dry powder product and a second dry powder product to a dry powder mixing apparatus, continuously feeding a product mixture consisting of the first and second dry powder products using the dry powder mixing apparatus, continuously feeding the product mixture to a production machine, continuously processing the product mixture using the production machine, and discharging the processed product from the production machine.

[0003] Solid dosage forms such as tablets or capsules or oral solid dosage forms (OSD) can be produced in tablet presses, e.g. rotary tablet presses, or capsule filling machines. In a continuous production line, for example a powder mixture of at least one active pharmaceutical ingredient (API) and at least one excipient is continuously provided by a mixer and fed to, e.g., a tablet press or capsule filling machine. The powder product mixed in the mixer can then be continuously fed to the inlet of the continuous production line. A feed dosing device may be provided to feed or dose the ingredients to be processed. Such a production process is also called direct processing and, in particular for tablet presses, also called direct compression process, in contrast to granulation processes using further equipment and processing steps, such as dry or wet granulators or intensive dryers, to improve processability such as flowability and compressibility of products not suitable for direct processing or to avoid segregation of the resulting mixture.

[0004] A system and a method for the continuous production of solid dosage forms are known, for example, from EP 3 013 571 A1. The components of the system, in particular the feeder, mixer and tablet press, are stacked vertically so that the product flows through the system via gravity from the feeder to the mixer and then to the tablet press. This results in a reliable, simple and cost-effective flow of the product through the system. However, the inventors have found that this system design, which is common throughout the field of continuous production of solid dosage forms, has certain disadvantages. One of the disadvantages is that the overall system height is rather high, more than 5 m. In practice, the height of the system can exceed 7 m. This makes it difficult to use standard production rooms for tablet compression or capsule filling, since special production rooms with the required room height are required. Additionally, the provision of specific operator platforms for operator access to system components such as feeding dosing or mixing equipment may make the system more complex and costly to design, complicate access and cleaning, and increase the overall footprint due to the use of stairs or platforms for operator access.

[0005] Alternatively, an operator platform may use a lift system in combination with an automatic coupling and uncoupling system to allow the operator access to the system components, which also adds complexity and cost to the design and use of the system.

[0006] EP 2 427 166 B1 discloses in one embodiment a self-contained module for producing tablets, which comprises a granulator mounted on a post hoist, which allows manual powder filling, cleaning, inspection, maintenance, and installation in a low vertical position and is hoisted up above a side-by-side dryer, allowing gravity feeding from the granulator to the dryer. Alternatively, a pneumatic conveying device may be provided to convey material from the granulator to the dryer and possibly from the dryer to a tablet press which is subsequently arranged. Thus, this module according to EP 2 427 166 B1 is not a direct compression module, but rather includes a granulator.

[0007] In direct processing systems, a major problem is that segregation of the resulting mixture may occur after mixing. For example, a single component may separate from the mixture because the particles of the component do not combine with the particles of other components during the granulation process. This can lead to an inhomogeneous mixture, with a too high or too low concentration of this component in the resulting mixture. This in turn can lead to quality problems in the produced solid dosage form. It is therefore preferable to feed the powder product directly from the mixing device via gravity to a production machine such as a tablet press, which leads to the above-mentioned disadvantages, especially regarding the height of the system. In indirect processing systems with granulators such as the modules described in EP 2 427 166 B1, such segregation problems are not particularly relevant, especially since the particles of the different components are combined throughout the granulation process.

[0008] Based on the above prior art, it is an object of the present invention to provide a system and a method for the continuous processing of powdered products, which can be manufactured, installed and used in a simple and cost-effective manner. The present invention solves this object with a system according to independent claim 1 and a method according to independent claim 28. The independent claims as well as the description and drawings contain advantageous embodiments.

[0009] As a system of the above type, the invention solves the object by having the outlet of the dry powder mixer at a lower level than the feed frame inlet of the machine, and a product conveying device located at the junction between the outlet of the dry powder mixer and the feed frame inlet of the machine, which product conveying device conveys the product mixture continuously from the outlet of the dry powder mixer to the feed frame inlet of the machine.

[0010] As a method of the above mentioned type, the invention solves the object in that the product mixture supplied by the dry powder mixer is fed to an outlet of the dry powder mixer which is arranged at a lower level than the feed frame inlet of the production machine for the product mixture, and that the product mixture is conveyed from the outlet of the dry powder mixer to the feed frame inlet of the production machine, with a product conveying device being arranged at the connection between the outlet of the dry powder mixer and the feed frame inlet of the production machine.

[0011] The system of the invention can for example produce solid dosage forms. The solid dosage forms that can be produced by the system and method of the invention are in particular oral solid dosage forms (OSD). These can be produced from dry powder materials that are fed to the system of the invention through the first and second inlets. As explained above, the invention may relate to a direct processing system and a direct processing method. In particular, in a system that includes a tablet press, this is also called a direct compression system and a direct compression method. In the system and method of the invention, preferably the direct processing system and the direct processing method, a first dry powder product, such as an active pharmaceutical ingredient (API), is continuously mixed with a second dry powder product, such as an excipient, in a mixing device. This mixing device is a dry powder mixing device. The product mixture produced in the dry powder mixing device is therefore a dry powder product mixture. In particular, the dry powder product mixture may be a non-binding dry powder product mixture. The mixing device is not a granulator, in particular does not comprise a chemical or mechanical granulation process. Immediately after the mixing step, the solid dosage form can be continuously produced in a manufacturing machine, for example by compressing the powder product into tablets in a tablet press. No additional equipment or steps, such as granulators or dryers or steps, are required. The systems and methods of the present invention do not specifically need to include granulators or methods, or dryers or methods.

[0012] The systems and methods of the present invention are for continuous processing of powder products. As such, they are continuous systems and processes. The systems and methods of the present invention may include intermittent process components or process steps.

[0013] The mixing device may be any type of dry powder mixer or dry powder mixing device operating continuously, the feed and discharge being preferably a continuous product flow. The mixing device may for example be a screw blender. The mixing device may comprise a mixing tube. The mixing tube may for example be arranged substantially horizontally. The inlet or inlets of the mixing device may be provided at the upper side of the mixing tube. The outlet may be located at the lower side of the mixing tube.

[0014] As already indicated, the first product may be, for example, an API. The second product may be, for example, an excipient. Of course, other than the first and second powder products may be provided and processed in the system and method of the invention, for example one or more further APIs and one or more further excipients, for example one or more lubricants. For this purpose, the system of the invention may comprise a number of inlets for mixing and processing the further powder products. The mixing device may have a joint inlet for the first and second powder products. However, the inlet of the mixing device connected to the first and second inlets for the first and second powder products may also comprise two separate inlets, one connected to the first inlet for the first powder product and one connected to the second inlet for the second powder product. The mixing device may also comprise further inlets for further powder products, such as further excipients, such as lubricants. The mixing device may comprise, for example, a first common inlet for the API and the first excipient and a second inlet for the further excipient, such as a lubricant. For example, if a common inlet is provided for the powder products from the first and second inlets, a hopper can be provided between the first and second inlets and the inlet of the mixer to collect and supply the materials to be mixed to the mixer.

[0015] The connections of the components of the system of the invention can be in the form of pipes or the like. The inlets and outlets of the system and its components are designed to be removable, and therefore can be removed from the respective connections. However, they may not be removable, and therefore are fixedly connected to the respective connections with which they are fitted, for example by being integrated into the respective connections. The inlets and outlets of the system and its components may have a closing device for closing the respective connections with which they are fitted. However, they may not be provided with such a closing device, and access to the respective connections is always free.

[0016] According to the invention, the outlet of the mixing device is located at a lower level than the powder feed frame inlet of the machine. The powder feed frame refers to the part of the machine where the powder material to be processed in the machine enters the machine and / or is collected before processing. For example, in a tablet press machine, the feed frame usually comprises a filler housing in which, for example, a rotating paddle is arranged, which keeps the powder in a fluidized state so that it can be filled into the die of the rotor of the tablet press. For example, in a capsule filling machine, the feed frame usually also comprises a filler housing in which the powder is collected before being filled into the capsules, in particular before being fed to a tamping station for slightly compressing the powder before being filled into the capsules. The feed frame inlet may be located, for example, inside the housing of the machine and above, for example, the feed frame of the tablet press or the tamping station of the capsule filling machine. The design of the invention requires that the product mixture provided to the outlet of the mixing device is raised to a higher level than the feed frame inlet of the machine. For this purpose, a product conveying device is provided, which conveys the powder product mixture from the outlet of the mixing device, which is located at a lower position, to the feed frame inlet of the machine, which is located at a higher position. The powder product conveying device thus raises the powder product mixture from a lower vertical position to a higher vertical position. The product conveying device may have an inlet at a lower position, which is connected to the outlet of the mixing device, and an outlet at a higher position, which is connected to the feed frame inlet of the machine. The inlets and outlets of the product conveying device may be arranged such that the powder mixture can flow via gravity from the outlet of the mixing unit to the inlet of the product conveying device and, once conveyed to the higher position, can flow via gravity from the outlet of the product conveying device to the feed frame inlet of the machine.

[0017] The inventors of the present invention have found that this design allows for reliable transport of the powder product mixture even in continuous direct processing systems and methods, and for example for reliable production of solid dosage forms from the powder mixture in a production machine that meets all quality requirements. In particular, the inventors have found that the design of the present invention with the powder product transport device allows for avoiding separation of the product mixture to the necessary extent. Based on this knowledge of the inventors, the present invention allows for the mixing device and the first and second inlets to be located next to the production machine, also in direct processing systems, instead of close to the production machine. The production machine and the mixing device as well as the first and second inlets, and possibly any further components of the system, can be installed at the same floor level, in particular at a much lower level compared to the systems of the prior art. Therefore, the system and method of the present invention can be easily and cost-effectively installed in existing standard production rooms, also for direct processing systems, without requiring major modifications or the construction of new production rooms. No operator platform is required to access certain components of the system. Also, no lifting devices or automatic coupling and uncoupling systems are required to lift and lower the components of the system. Thus, the system of the present invention can be provided without such lifting devices, automatic coupling and uncoupling systems, or operator platforms for accessing the components of the system of the present invention, for example, for installation, disassembly, cleaning, maintenance, or repair. Rather, the system generally provides better accessibility and ergonomics for set-up, inspection, cleaning, disassembly, maintenance or repair, and product changeover. Furthermore, the absence of an operator platform reduces the footprint of the production line. The system of the present invention is more compact and easier and faster to install and start up. At the same time, all the advantages of continuous direct processing systems and methods can be realized. Compact devices such as the system of the present invention can also be made mobile, so that they can be moved from one production room to another.The powder conveying system of the present invention allows, for example, the mixing device and possibly the dosing device to be located away from the production machine in the same room or in an adjacent room. It is easy to incorporate powder diversion mechanisms between the mixing device and the production machine to eliminate off-spec material. Of course, the system of the present invention is also more cost-effective compared to the multi-level complex systems of the prior art.

[0018] The system of the present invention may be a containment system having a containment level of product toxicity OEB3 or higher (eg, as measured by SMEPAC (Standardized Measurement of Equipment Particulate Airborne Concentration) testing).

[0019] According to one embodiment, the continuous processing of the powder product is the continuous production of solid dosage forms in a direct process, where a manufacturing machine is provided for the continuous production of solid dosage forms from the product mixture and has an outlet for discharging the produced solid dosage forms. The manufacturing machine is thus capable of discharging the solid dosage forms as processed products. Thus, the product discharged according to the method of the present invention may be a solid dosage form. The manufacturing machine may be a tablet press or a capsule filling machine. Thus, the solid dosage form may be a tablet or a capsule. The tablet press may in particular be a rotary tablet press.

[0020] The manufacturing machine may be a different manufacturing machine, such as a granulator. The granulator is fed with a dry powder output mixture from a dry powder mixer for the purpose of binding the single components together. The granulator may be a dry granulator or a wet granulator. In a dry granulator, the binding is by compression. In a wet granulator, the binding is by a binder such as water or a solution. The dry granulator may be, for example, a roller compactor. In any case, the powder product conveying device of the present invention conveys the dry powder output mixture.

[0021] The system of the invention may also include one or more manufacturing machines and / or one or more dry powder mixers, and one or more product conveying devices of the invention may be provided between each dry powder mixer and each manufacturing machine downstream of each dry powder mixer.

[0022] According to a further embodiment, the first inlet for the first powder product and the second inlet for the second powder product can be arranged at a position not higher than the production machine or the product conveying device. The first and second inlets may in particular be arranged so as not to extend to a height above the production machine or the product conveying device. The product conveying device or its outlet for discharging the transported product mixture to the supply frame inlet of the production machine may extend higher than the supply frame inlet of the production machine. In this case, the first and second inlets may be arranged not to be higher than the product conveying device or its outlet. If further inlets for further powder products are provided, this embodiment is equally applicable to these. The above-mentioned embodiment provides a further reduction in height.

[0023] According to a further embodiment, a feed dosing device may be connected to the first and second inlets for the first and second powder products, respectively, and to the inlet of the mixer. The feed dosing device may, for example, be a loss-in-weight feeder. A feed dosing device may be arranged at each connection of the first and second inlets and the inlet of the mixer.

[0024] According to further embodiments, the dosing devices may be arranged in one, two or more rows, in particular along one, two or more horizontal axes. If more than one row of dosing devices is provided, the rows may for example be arranged along parallel horizontal axes. Such an arrangement leads to a more compact design compared to the circular arrangement proposed in the prior art.

[0025] According to a further embodiment, the dosing device can be arranged at a position not higher than the production machine or the product conveying device. The dosing device may in particular be arranged so that it does not extend to a height above the production machine or the product conveying device. The dosing device may also be arranged beside the production machine. The product conveying device or its outlet for discharging the transported product mixture into the feed frame inlet of the production machine may extend higher than the feed frame inlet of the production machine. In this case, the dosing device may be provided not higher than the product conveying device or its outlet.

[0026] According to a further embodiment, which is particularly compact in design, the dosing device together with the mixing device may form a dosing and mixing module. The dosing and mixing module may be arranged in a module housing. This embodiment also allows for easy compliance with containment requirements. The provision of the dosing and mixing module also allows for mobility of the module, so that the dosing and mixing module can be moved from one production site to another, for example from one production site to another. The module housing may be at the same height as the machine housing or may be lower.

[0027] According to a further embodiment, the module housing may form the system housing together with the housing of the production machine, for example the tablet press housing or the capsule filling machine housing, and thus the module housing is integrated or connected to the production machine housing, which allows a particularly compact design and further allows the containment requirements to be easily met.

[0028] According to a further embodiment, the height difference between the outlet of the mixer and the inlet of the feed frame of the machine may be greater than 0.50 m, preferably greater than 1 m, more preferably greater than 1.50 m. According to a further embodiment, the product mixture may be transported by the product conveying device from the outlet of the mixer to the inlet of the feed frame of the machine over a height difference which may be greater than 0.50 m, preferably greater than 1 m, more preferably greater than 1.50 m. This height difference corresponds to the vertical rise of the product mixture that the product conveying device must carry out. Preferably, the difference may be about 2 m.

[0029] According to a further embodiment, the total height of the system may be less than 3.50 m, preferably less than 3 m, more preferably less than 2.50 m. The total height indicates the height from the floor level on which the system is installed to the first and second inlets of the system. Such a low height of the system is possible due to the design of the system of the invention, allowing the use of standard rooms with improved accessibility to the components of the system.

[0030] According to a further embodiment, the product conveying device may be a pneumatic product conveying device, for example a vacuum-tight phase product conveying device. Such a conveying device is particularly suitable for the purpose of the present invention, which is to convey the mixed powder material from the mixer outlet to the feed frame inlet of the manufacturing machine without critical separation. Segregation during conveying generally occurs because the powder particles differ primarily in size, shape and / or density. Thus, a first dry powder product may differ in size, shape and / or density from a second dry powder product. Granulation attempts to solve the segregation by combining different single components, effectively producing particles of the same size, shape and density. However, in some manufacturing systems, it may not be desirable to add a granulator, or it may be necessary to convey the powder mixture from the dry powder mixer before entering the granulator. The inventors of the present invention have found that, in particular with a vacuum-tight phase product conveying device, the dry powder mixture does not segregate significantly during conveying.

[0031] Preferably, the product conveying device, for example a vacuum-tight phase product conveying device, may comprise a hose for conveying the product mixture. Due to its simple, smooth internal shape and large radius of curvature, the flexible hose allows a flexible connection between the dry powder mixer and the production machine, with minimal impact on the powder conveying process and / or the control of the conveying process or only minor adjustments to the control. The hose, which is powder-tight under vacuum, can also advantageously act as a buffer against upstream disturbances in the downstream process. Due to upstream disturbances, such as the stoppage of the refill system, the stoppage of the dosing device or the stoppage of the mixer, components upstream of the hose may temporarily become empty. In such cases, the powder remaining in the hose ensures that the production machine continues to operate normally. When the powder flows normally again, due to the dense powder and the vacuum in the hose, the hose automatically fills with powder without affecting the downstream process.

[0032] According to a further embodiment, the ratio of hose length to hose diameter may be at least 25, preferably at least 50, more preferably at least 100. Thus, the hose has a relatively small diameter compared to its length. By using a hose with a small diameter, the friction of the powder in the hose is increased. This in turn makes the powder in the hose more degassed and dense, facilitating the formation of a powder plug and subsequent air plug in the hose. Powder plug formation, the phenomenon in which the powder in the hose becomes a powder plug followed by an air plug, occurs when the pressure in the conveying hose is reduced, i.e. the vacuum level is increased. The denser powder plug further reduces the movement of the fine components into and fixes the matrix of the coarser components of the powder material, further reducing the movement of air through the plug during conveying. The movement between particles in the powder plug and the air through the powder plug is further reduced, which further reduces segregation. Furthermore, the use of a hose of sufficient length allows for a flexible arrangement of the conveying unit and the manufacturing machine, which further reduces the footprint of the system and allows the system to be arranged in a smaller room or the individual components of the system to be arranged in different rooms. Additionally, in systems that continuously manufacture solid dosage forms, lot genealogy and product tracking for advanced process control are very important. Lot genealogy here refers to the concept of tracking all raw material batches to the final dosage form so that if an out-of-specification raw material batch is identified, the final dosage form can be identified and, if necessary, withdrawn from the market and discarded. Advanced process control here refers to the concept of combining different process decisions in time and space for the same in-process product to improve process measurements and process understanding. Advanced process control here may also refer to the use of feed-forward or feedback control loops, where process changes or actions on the product are made before or after the product is measured. To enable reliable product tracking, product backmixing should be minimized or, if possible, product first-in-first-out (FIFO) flow should be maximized.Small diameter hoses further improve product flow in the FIFO, and smaller hose diameters and / or longer hose lengths allow for greater pressure drop in the conveying line, if desired.

[0033] As already mentioned, the product conveying device may be a vacuum-tight phase product conveying device. The solids loading of the pneumatic vacuum-tight phase product conveying device may be more than 15, preferably more than 30, more preferably more than 60. The solids loading is defined as the ratio of the solids flow rate conveyed to the air mass flow rate used. The inventors have found that such a solids loading is particularly advantageous for minimizing segregation. The solids loading can be measured, for example, at the outlet of the hose, and thus at the higher end of the hose. The outlet of the hose may be connected directly or indirectly to the feed frame inlet of the machine. For example, the hose is connected directly to the outlet hopper of the hose, where the powder mixture is transferred to the feed frame inlet of the machine.

[0034] It should be noted that the vacuum level in the conveying line of the vacuum-tight phase product conveying device, e.g. the product conveying hose for conveying the product mixture, decreases over the length of the conveying line, being substantially atmospheric pressure at the inlet of the conveying line and the highest vacuum at the outlet of the conveying line. According to a further embodiment, the pressure drop in the conveying line of the pneumatic vacuum-tight phase product conveying device, e.g. over the length of the hose for conveying the product mixture, may be greater than 0.5 bar, preferably greater than 0.7 bar, more preferably greater than 0.9 bar. The absolute pressure at the outlet of the conveying line, e.g. the hose, may be less than 0.5 bar absolute, preferably less than 0.3 bar absolute, more preferably less than 0.1 bar absolute. Thus, a (ultra) high vacuum is generated in the body of the vacuum-tight phase product conveying device. Typically, in vacuum conveying, a small amount of air (by creating an opening to the surroundings so that the air can be drawn in or by adding compressed air) is added to the powder flow at the inlet of the conveying system to help the formation of a powder plug and reduce the powder wall friction in the conveying line. The use of high vacuum in the above described embodiment ensures that the powder plug can be transported without the need for excess aeration or compressed air. The powder is transported through the plug with minimal air movement without the need for additional air. This in turn minimizes particle to particle movement and air passing through the powder, effectively minimizing segregation.

[0035] According to a further embodiment, an inlet hopper may be provided at the inlet of the product conveying device, preferably with a conical narrowing towards the diameter of the conveying line of the product conveying device, e.g. the product conveying hose, so that as the powder material is further degassed and densified, the fine components are immobilized in a matrix of the coarser components, further reducing the movement of air through the powder material during conveyance, further reducing the movement between particles and the air through the powder, thereby further reducing segregation.

[0036] As known to those skilled in the art, vacuum transfer may be an intermittent process. Intermittent vacuum transfer typically consists of the following cycles: Creating a vacuum at the outlet of a conveying line such as a hose or pipe; conveying the product through a conveying line by means of a vacuum; opening a discharge valve in the delivery line to discharge the product from an outlet of the delivery line; Closing the discharge valve; Repeat the cycle.

[0037] Thus, the vacuum product delivery line has a number of cycles. In each cycle, a certain powder portion is delivered together through the product delivery device having a certain cycle volume and cycle mass. The powder portion delivered in each cycle through the vacuum product delivery line may consist of one or more powder plugs.

[0038] By increasing the cycle times of the product conveying device, the cycle time is shortened and the conveyed volume of the conveyed powder portion is reduced. By reducing the conveyed volume, the impact on upstream and downstream processes can be minimized. For upstream processes, e.g. for the feeding dosing device, a smaller powder volume means smaller fluctuations in the powder level at the inlet of the product conveying device, which leads to smaller air pressure fluctuations at the outlet of the feeding dosing device. For downstream processes, e.g. for the feeding frame of the manufacturing machine, a smaller powder volume means smaller fluctuations in the powder level and powder pressure at the feeding frame inlet, which leads to minimized fluctuations in the feeding process of the manufacturing machine. According to a further embodiment, the cycle mass may be 2 kg or less, preferably 1 kg or less, more preferably 0.5 kg or less. The cycle mass can be calculated from the cycle time and the mass flow rate (powder throughput of the system (kg / h)) as follows: Cycle mass (kg) = cycle time (h) x mass flow rate (kg / h)

[0039] A high speed circulation conveying device with a small conveying volume allows the use of small inlet and outlet hoppers. The inlet and outlet hopper volumes can be calculated from the cycle mass and powder density. Since the powder is injected into the hopper, this is called the injection density. Hopper volume (liters) = cycle mass (kg) ÷ powder density (kg / liter)

[0040] According to a further embodiment, an inlet hopper may be provided at the inlet of the product conveying device and / or an outlet hopper may be provided at the outlet of the product conveying device. The volume of the inlet hopper and / or the outlet hopper may be 7 liters or less, preferably 3 liters or less, more preferably 0.5 liters or less, respectively. By minimizing the buffer formed by the inlet hopper and the outlet hopper, pile separation is minimized, vibration separation is minimized, shear separation is minimized, air separation is minimized, and therefore separation is minimized.

[0041] According to a further embodiment, an inlet hopper may be provided at the inlet of the product conveying device, the inlet hopper having an inlet hopper half angle of less than 45 degrees, preferably less than 30 degrees, more preferably less than 20 degrees. The inlet hopper may be, for example, conical. The hopper half angle is measured between the hopper wall, for example a conical hopper wall, and the central axis of the hopper. Thus, the smaller the hopper half angle, the steeper the hopper half angle. A steeper hopper half angle prevents rat-holing and further minimizes segregation and shear separation by promoting powder mass flow rate. Mass flow rate also further improves the product flow of the FIFO. A steeper hopper half angle results in a smaller hopper inlet diameter for a given hopper volume. Reducing the hopper inlet diameter can further minimize segregation.

[0042] According to a further embodiment, an outlet hopper may be provided at the outlet of the product conveying device, where the ratio of height to diameter of the outlet hopper is at least 2, preferably at least 5, more preferably at least 10. Preferably, the outlet hopper may be cylindrical. Such a geometry further minimizes segregation.

[0043] In the outlet hopper, positive pressure may be applied, for example, after opening the outlet hopper discharge. By using an outlet hopper with a small diameter, resulting in a long or long length, friction of the powder in the outlet hopper increases. By using positive pressure in the outlet hopper, friction of the powder can be reliably eliminated and the powder can be discharged from the outlet hopper.

[0044] Other conveying devices are generally also feasible, for example the conveying device may be a powder pump, preferably a powder film pump or an air diluted phase product conveying device, or it may be a screw conveying device, for example a rigid or flexible screw conveying device, or for example a bucket lift conveyor, a disk conveyor system or a transport belt.

[0045] According to further embodiments, the feed frame inlet may be equipped with a vent, preferably with a dust remover, and more preferably without a filter. The product conveying device intermittently feeds and discharges a quantity of powder to the inlet of the feed frame of the machine. When the discharge valve of the product conveying device closes, the powder level at the inlet of the feed frame is reduced or reduced. Due to the closed or sealed system, this causes a pressure shortage at the feed frame inlet and the feed frame. This can have a negative effect on the supply of powder to the machine and can cause undesirable supply fluctuations. To avoid this low pressure, a vent is added to the feed frame inlet. Typically, an air filter (more specifically a particulate air filter to remove particulate matter from the air) is added to maintain containment and prevent powder from escaping from the system. However, particulate air filters have disadvantages, especially in this regard. On the one hand, the filter is prone to accumulation of fine powder against the filter material. If this fine powder falls off the filter material again, it can cause demixing and separation of the fine powder. On the other hand, the filter reduces the pressure as the air passes through the filter material. This pressure drop becomes even greater when the filter becomes clogged with powder. Depending on the direction of air flow through the filter, this pressure drop across the filter can result in over or under pressure in the system.

[0046] It is therefore particularly preferred to provide the vent without a filter. To ensure that no powder escapes through the vent, the vent may comprise a (preferably vertical) vent pipe of sufficient length and an actual vent at the top. The air volume in the vent pipe may be at least as large as the powder conveyed volume. When a certain amount of powder is filled at the feed frame inlet, air (possibly dust-laden air) can enter the vent pipe, but essentially does not leave the vent pipe and enter the surrounding environment. In the next step of the conveying cycle, lowering the powder level at the feed frame inlet will cause the (dust-laden) air in the vent pipe to return. The air movement effectively follows the cycle of the product conveyor, with the air volume increasing (during powder discharge) and decreasing (when the mixing conveyor outlet valve is closed) in the vent pipe, but no air actually leaks out. As a safety measure, a dust removal shroud or dust removal nozzle (connected to a vacuum cleaner or a centralized dust removal system) may be installed over the vent pipe, especially over the vent, to ensure that no dust-laden air or powder escapes through the vent pipe. It is not directly connected to the vent pipe, but is placed a small gap above the vent pipe. This shroud or nozzle extracts dust that may escape the vent pipe due to preferential air flow in the vent pipe, powder entrainment, or long term transient effects.

[0047] The inlet hopper of the product conveying device may also be equipped with a vent, which preferably does not have a particle filter as described above for the feed frame inlet of the machine. A similar intermittent cyclic process of rising and falling powder levels exists in the inlet hopper of the product conveying device as in the feed frame inlet. The inlet hopper is continuously fed with powder by the dry powder mixer and intermittently emptied by the product conveying device, effectively causing the powder in the inlet hopper to rise (slow) and fall (fast). This can also cause pressure fluctuations at the outlets of the mixer and the feed dosing device. The vent in the inlet hopper avoids pressure fluctuations at the outlet of the feeder, pressure rise during filling of the inlet hopper, and pressure drop during discharge of the inlet hopper.

[0048] The mixing device, the product conveying device, the first and second inlets and / or possibly the dosing device can be controlled via individual control units or a central control unit. For example, the above-mentioned components can be controlled by the same control device as the manufacturing machine, e.g. the control unit of a tablet press or capsule filling machine. This makes the system particularly easy to control while still allowing remote operation from a separate room and further improves operator safety.

[0049] The methods of the invention can be carried out using the systems of the invention. Thus, the systems of the invention can be designed to carry out the methods of the invention.

[0050] Embodiments of the invention are explained in more detail below with reference to the drawings. [Brief description of the drawings]

[0051] [Figure 1] FIG. 1 is a first perspective view of a system according to a first embodiment of the present invention. [Diagram 2] FIG. 2 is another perspective view of the system shown in FIG. 1 . [Diagram 3] FIG. 4 is a perspective view of a system according to a second embodiment of the present invention. [Figure 4] FIG. 4 is an enlarged view of detail A of FIG. 3. [Diagram 5] Enlarged view of detail B of Figure 3. [Figure 6] FIG. 13 is a perspective view of a system according to a third embodiment of the present invention.

[0052] In the drawings, like reference numbers refer to like parts.

[0053] 1 and 2 show a system of the invention for the continuous production of solid dosage forms in a direct process according to a first embodiment. The system comprises a production machine 10, which in the illustrated example is a rotary tablet press 10. The tablet press 10 is arranged in a production machine housing 12, which in the illustrated example is a tablet press housing 12. The tablet press housing 12 is integrated with a module housing 14 and contains a feed-dosing mix module, which will be described in more detail below. The tablet press housing 12 together with the module housing 14 form a system housing 16. The system housing 16 has a number of windows 18, which are openable to access the components of the system. While in FIG. 1 the windows 18 are shown in a closed position, in FIG. 2 the windows 18 are shown in an open position in order to better illustrate the components of the system. The lower part of the module housing 14 is further cut away in FIG. 2 to better understand the design of the system. As can be seen in the example of FIG. 1, the tablet press housing 12 and the module housing 14 are approximately the same height. Visible at the top of the system housing 16 is the outlet 20 of the system's product conveyor 22. The inlet of the product conveyor 22 is visible in FIG.

[0054] In FIG. 2, a first inlet 26 for a first powder product, such as an API, and a second inlet 28 for a second powder product, such as an excipient, are visible. Furthermore, in FIG. 2, a third inlet 30 for a third powder product and a fourth inlet 32 ​​for a fourth powder product are visible. The third powder product may be, for example, another API or another excipient. The fourth powder product may be, for example, an excipient, such as a lubricant. Each inlet 26, 28, 30, 32 is connected to a subsequent feed dosing device 34, 36, 38, 40 via a refill system 42, 44, 46, 48. Each feed dosing device 34, 36, 38, 40 may be a loss-in-weight feeder. As can be seen in FIG. 2, the feed dosing devices 34, 36, 38, 40 are arranged in a row, in particular along a horizontal axis.

[0055] The feed dosing devices 34, 36, 38, 40 are in turn connected to a mixing device 50. The mixing device 50 may generally be any type of dry powder mixer or blender. The mixing device 50 has a first inlet 52 connected to the feed dosing devices 34, 36, 38. A second inlet 54 of the mixing device 50 is connected to the feed dosing device 40. The mixing device 50 further has an outlet 56 connected to the inlet 24 of the product conveying device 22. The outlet 20 of the product conveying device 22 is connected to a feed frame inlet 58 of a feed frame 60 of the tablet press 10. The outlet 20 of the product conveying device 22 and the feed frame inlet 58 of the feed frame 60 of the tablet press 10 are connected via a vertical tube 62. The tablet press 10 further has an outlet 64 for discharging the produced tablets.

[0056] The method of the present invention, carried out using the system of the present invention, is described below. During production, the first, second and third powder products, which are fed to the first, second and third inlets 26, 28, 30, are continuously fed to the first inlet 52 of the mixer 50 through the feed and dosing devices 34, 36, 38. The fourth powder product, which is fed to the fourth inlet 32, is continuously fed to the second inlet 54 of the mixer 50 through the feed and dosing device 40. The mixer 50 continuously produces and feeds a powder product mixture of the four powder products at its outlet 56. The product mixture is continuously fed to the inlet 24 of the product conveying device 22. As can be seen for example in FIG. 2, the inlet 24 of the product conveying device 22 is located below the outlet 56 of the mixer 50, so that the product mixture can flow by gravity from the outlet 56 to the inlet 24. As can be further seen in Figure 2, the outlet 56 of the mixing apparatus 50 and of course the inlet 24 of the product conveying apparatus 22 are located at a lower level than the feed frame inlet 58 of the tablet press 10 and lower than the outlet 20 of the product conveying apparatus 22, which is located above the feed frame inlet 58 of the tablet press 10. The product conveying apparatus 22 continuously conveys the product mixture fed from its inlet 24 to its outlet 20, thus vertically raising the product mixture to a higher level. The elevated product mixture is continuously fed by gravity from the outlet 20 to the feed frame inlet 58 of the tablet press 10, which continuously produces tablets from the fed product mixture and discharges the produced tablets from its outlet 64.

[0057] According to the design of the system described above, the total height of the system can be limited to less than 3.50 m, preferably less than 3 m, more preferably less than 2.50 m. For this purpose, the product mixture may be raised vertically by the product conveying device 22 over a height of more than 1.50 m, for example approximately 2 m. It is visible in Figures 1 and 2 that the inlets 26, 28, 30 and 32 of the system, and thus also the feed dosing devices 34, 36, 38 and 40, are arranged so as not to extend beyond the height of the product conveying device 22 with the outlet 20. The design of the system and method described above results in a particularly compact structure which, as mentioned above, can be easily installed and improves access to the components of the system.

[0058] In Figures 3 to 5 a second embodiment of the system of the invention is shown, which is broadly similar to the system shown in Figures 1 and 2. It also comprises a feeding, dosing and mixing module arranged in a module housing 14, and a manufacturing machine 10 arranged in a manufacturing machine housing 12. The manufacturing machine 10 may be, for example, a tablet press, such as a rotary tablet press. However, the manufacturing machine 10 may also be, for example, a capsule filling machine or another manufacturing machine.

[0059] In the embodiment shown in Figures 3 to 5, the module housing 14 is provided with two doors 66 for accessing the inside of the module housing 14, instead of the windows 18 of Figures 1 and 2. In Figure 3, the doors 66 are shown in an open position in order to better illustrate the components of the system. At the top of the machine housing 12, the outlet 20 of the product conveying device 22 of the system is visible. The inlet 24 of the product conveying device 22 is again visible near the outlet 56 of the mixer 50. A conical inlet hopper 68 is arranged at the inlet 24 of the product conveying device 22. Connected to the inlet hopper 68 of the product conveying device 22 is a flexible product conveying hose 70 for conveying the product mixture leaving the mixer 50 in a vacuum-tight manner. In the enlarged view of Figure 5, the conical reduced diameter portion 72 of the inlet hopper 68 is visible.

[0060] The vacuum tight phase product conveyor 22 shown in Figures 3 to 5 further comprises a flexible vacuum hose 74 and a vacuum generator 76. The vacuum generator 76 generates a vacuum at the outlet 20 of the product conveyor hose 70 through the vacuum hose 74 which conveys the product mixture through the product conveyor hose 70 from the inlet 24 to the outlet 20 of the product conveyor 22. At the outlet 20 of the product conveyor hose 70, a discharge valve is intermittently opened and closed to discharge the conveyed product mixture into the feed frame inlet 58 of the machine 10. For this purpose, an outlet hopper 69 is provided at the outlet 20 of the product conveyor 22.

[0061] As mentioned above, this intermittent conveying process causes the powder level to intermittently rise and fall at the feed frame inlet 58 of the machine 10. To avoid undesirable low pressure in the feed frame inlet 58, a vertical vent pipe 78 having a vent opening at the top of the pipe is provided at the feed frame inlet 58 of the machine 10. A dust shroud 80 and dust hose 82 are provided at the top of the pipe 78 and lead to a dust extraction system which extracts any dust that may escape the pipe 78 through the vent opening.

[0062] Similar problems with pressure build-up and drop due to intermittent conveying exist in the inlet hopper 68 of the product conveying system 22, so a corresponding vent pipe 78 having a vent opening at the top thereof is disposed in the inlet hopper 68, as can be seen in FIG. 5.

[0063] To supply the dry powder product to the dry powder mixing device 50, the system shown in figures 3 to 5 further comprises a first inlet 26 for a first powder product, such as an API, a second inlet 28 for a second powder product, such as an excipient, and a third inlet 30 for a third powder product. The third powder product may again be, for example, another API or another excipient. Each inlet 26, 28, 30 is again connected to a subsequent feed dosing device 34, 36, 38 via a refill system 42, 44, 46. Behind the feed dosing devices 34, 36, 38 further technical components, such as drives, are arranged, which are only partially shown in figure 3 in housings 84, 86, 88. The rear wall 90 of the module housing 14 is also visible in figure 3.

[0064] The manufacturing process using the system shown in Figures 3-5 is essentially the same as that described above for Figures 1 and 2. Powder product is continuously fed through inlets 26, 28, 30, through refill systems 42, 44, 46, through feed dosing devices 34, 36, 38, through hopper 92, and at inlet 52 of mixer 50. The dry powder product fed to mixer 50 is continuously mixed in dry powder mixer 50 and discharged through outlet 56 of mixer 50 to inlet 24 of product conveyer 22, specifically to inlet hopper 68. Vacuum tight phase product conveyer 22 conveys the resulting mixture through product conveying hose 70 to feed frame inlet 58 of machine 10, as described above. Machine 10 continuously processes the resulting mixture into products, such as solid dosage forms, such as tablets and capsules. The manufactured products are discharged from machine 10 through outlet 64.

[0065] A further embodiment of the system of the invention is shown in FIG. 6. The system shown in FIG. 6 comprises two feed-dosing and mixing modules arranged in two module housings 14. The feed-dosing and mixing modules with their module housings 14 can be implemented as described with respect to the system shown in FIG. 3 to FIG. 5. In FIG. 6, the door 66 of the module housing 14 is closed. A further difference between the system shown in FIG. 6 and the system shown in FIG. 3 to FIG. 5 is that the system according to FIG. 6 comprises two machines 10, each arranged in a machine housing 12. The machine 10 shown on the left side of FIG. 6 may be, for example, a tablet press, such as a rotary tablet press, or a capsule filling machine. The machine 10 shown between the two feed-dosing and mixing modules may be, for example, a roller compactor or a similar granulating device. In the first feed-dosing and mixing module shown on the right hand in FIG. 6, different dry powder products are mixed successively in a dry powder mixing device 50, as described with respect to the above embodiment. This powder mixture is then conveyed through a product conveying hose 70 of the product conveying device 22 of the first feeding, dosing and mixing module, which is again a vacuum-tight phase product conveying device, to a feed frame inlet of a subsequent first manufacturing machine 10, which is for example a granulator. In this granulator, the product mixture is granulated to produce a granulated product. The granulated product is then conveyed through a conventional granule conveying device 94, which may be any suitable granule conveying device, to one of the inlets 26 of a subsequent second feeding, dosing and mixing module. Further products may enter this second feeding, dosing and mixing module via further inlets 28 and / or 30. The supplied powder product, which may include granular product, is then continuously mixed in the dry powder mixer 50 of the second feeding, dosing and mixing module and subsequently conveyed through the powder conveying hose 70 of the product conveying device 22 of the second feeding, dosing and mixing module, again a vacuum tight phase product conveying device, to the feed frame inlet of the second machine 10, e.g. a tablet press or capsule filling machine. In the second machine 10, products are produced from the supplied powder mix, e.g. tablets or capsules, which are discharged from the outlet 64.

[0066] Like the systems shown in Figures 1 and 2 and 3 to 5, the system shown in Figure 6 also operates continuously.

[0067] Additionally, all of the systems shown in the drawings may be containment systems having a containment level of, for example, a product toxicity level of OEB 3 or greater, as measured, for example, according to the SMEPAC test. [Explanation of symbols]

[0068] 10…Manufacturing machine 12... Manufacturing machine housing 14…Module housing 16…System housing 18…Window 20...Outlet of product conveying device 22...Product conveying device 24...Inlet of product conveying device 26…First entrance 28...Second entrance 30…Third entrance 32...Fourth Entrance 34, 36, 38, 40...Supply dosing device 42, 44, 46, 48…Refill system 50…Mixing device 52...First inlet of mixing device 54...second inlet of mixing device 56...Outlet of mixing device 58…Manufacturing machine supply frame inlet 60… Manufacturing machine supply frame 62…Vertical tube 64…Exit of the manufacturing machine 66…Door 68…Inlet hopper 69…Exit hopper 70...Product transport hose 72…Conical narrowing section 74…Vacuum hose 76…Vacuum generator 78…Ventilation pipe with vent 80…Dust removal shroud 82…Dust removal hose 84, 86, 88…Housings for technical components 90…Back wall

Claims

1. A system for continuously processing powder products, said system comprising a first inlet (26) for a first dry powder product, a second inlet (28) for a second dry powder product, and a dry powder mixer (50) for continuously feeding a product mixture consisting of said first and second dry powder products, said dry powder mixer (50) comprising an inlet (52) connected to said first inlet (26) for said first powder product and said second inlet (28) for said second powder product and an outlet (56) for said product mixture, further comprising a production machine (10) comprising a powder feed frame (60) having a feed frame inlet (58) connected to the outlet (56) of said dry powder mixer (50), and an outlet (64), The dry powder mixer (50) is disposed next to the manufacturing machine (10), a product conveying device (22) located at a connection between the outlet (56) of the dry powder mixer (50) and the feed frame inlet (58) of the machine (10); and a product conveying device (22) for conveying the product mixture, the product conveying hose (70) having a ratio of a length of the product conveying hose (70) to a diameter of the product conveying hose (70) of at least 25, thereby increasing friction of the product mixture inside the product conveying hose (70) and degassing the product mixture inside the product conveying hose (70) to increase density and prevent separation of the product mixture, the product conveying device (22) conveying the product mixture continuously from the outlet (56) of the dry powder mixer (50) to the feed frame inlet (58) of the machine (10).

2. 2. The system of claim 1, wherein the continuous processing of a powder product is the continuous production of a solid dosage form in a direct process, and the manufacturing machine (10) is provided for the continuous production of a solid dosage form from the product mixture and has an outlet (64) for discharging the produced solid dosage form.

3. 3. The system according to claim 2, characterized in that the manufacturing machine (10) is a tablet press (10) or a capsule filling machine (10).

4. The system according to claim 1, characterized in that the manufacturing machine (10) is a granulator (10).

5. 5. The system according to claim 1, wherein the first inlet (26) for the first powder product and the second inlet (28) for the second powder product are arranged at a position not higher than the production machine (10) or the product conveying device (22).

6. 6. The system according to claim 1, wherein the height difference between the outlet (56) of the dry powder mixer (50) and the feed frame inlet (58) of the machine (10) is greater than 0.50 m.

7. 7. A system according to claim 1, characterized in that the total height of the system is less than 3.50 m.

8. 2. The system of claim 1, wherein the pneumatic vacuum tight-phase product conveyor (22) has a solids loading of more than 15.

9. 9. The system according to claim 1, characterized in that the pressure drop in the conveying line of the pneumatic vacuum-tight phase product conveying device (22) is greater than 0.5 bar.

10. 10. The system according to claim 1, characterized in that the cycle mass of the pneumatic vacuum-tight phase product conveying device (22) is less than or equal to 2 kg.

11. 11. The system according to claim 1, characterized in that an inlet hopper (68) is provided at the inlet (24) of the product conveying device (22).

12. 12. The system according to claim 1, characterized in that an inlet hopper (68) is provided at the inlet (24) of the product conveying device (22) and / or an outlet hopper (69) is provided at the outlet (20) of the product conveying device (22), the volume of the inlet hopper and / or the outlet hopper (68, 69) being less than or equal to 7 liters.

13. 13. The system according to claim 1, wherein an inlet hopper (68) is provided at the inlet of the product conveying device, the inlet hopper having a half angle of less than 45 degrees.

14. 14. The system according to claim 1, characterized in that an outlet hopper (69) is provided at the outlet (20) of the product conveying device (22), the outlet hopper (69) having a height to diameter ratio of at least 2.

15. 15. The system of claim 14, characterized in that a positive pressure is applied to the outlet hopper (69).

16. 16. The system according to claim 1, characterized in that the product conveying device (22) is a powder pump.

17. 17. The system according to claim 1, wherein the supply frame inlet (58) is provided with a vent (78).

18. 18. The system according to claim 1, wherein the inlet hopper (68) of the product conveying device (22) is provided with a vent (78).

19. 19. The system of claim 17 or 18, characterized in that the vent (78) comprises a vent pipe (78).

20. 20. The system according to claim 17, wherein the vent (78) comprises a dust shroud (80).

21. 21. The system according to claim 1, characterized in that a feeding dosing device (34, 36, 38, 40) is connected to the first and second inlets (26, 28) for the first and second dry powder products, respectively, and to the inlet (52) of the dry powder mixer (50).

22. 22. The system according to claim 21, characterized in that the feeding dosing devices (34, 36, 38, 40) are arranged in one, two or more rows.

23. 23. The system according to claim 21 or 22, characterized in that the dosing devices (34, 36, 38, 40) together with the dry powder mixer (50) form a dosing mixing module.

24. 24. The system of claim 23, wherein the module housing (14) together with a housing (12) of the machine (10) forms a system housing (16).

25. A method for continuously processing a powder product, comprising the steps of continuously feeding a first dry powder product and a second dry powder product to a dry powder mixer (50), continuously feeding a product mixture of the first and second dry powder products using the dry powder mixer (50), continuously feeding the product mixture to a production machine (10), continuously processing the product mixture using the production machine (10), and discharging the processed product from the production machine (10), The product mixture supplied by the dry powder mixer (50) arranged beside the manufacturing machine (10) is supplied to an outlet (56) of the dry powder mixer (50) arranged at a lower position than a feed frame inlet (58) of the manufacturing machine (10) for the product mixture, and a product conveying hose (70) for conveying the product mixture, the ratio of the length of the product conveying hose (70) to the diameter of the product conveying hose (70) being at least 25, thereby increasing the friction of the product mixture inside the product conveying hose (70) and wherein the product mixture is continuously conveyed from the outlet (56) of the dry powder mixer (50) to the feed frame inlet (58) of the machine (10) by a product conveying device (22) disposed at a connection between the outlet (56) of the dry powder mixer (50) and the feed frame inlet (58) of the machine (10), the product conveying device (22) comprising a product conveying hose (70) for degassing the product mixture inside the product conveying hose (70) to increase density and prevent separation of the product mixture.

26. 26. The method according to claim 25, characterized in that the method is for continuous production of solid dosage forms in a direct process, the solid dosage forms being continuously produced from the product mixture using the production machine (10) and being continuously discharged from the production machine (10).

27. 27. The method of claim 26, wherein the solid dosage form is a tablet or a capsule.

28. A method according to one of claims 25 to 27, characterized in that the method is carried out using a system according to one of claims 1 to 24.

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