RU2441696C2 - Granules, pills and granulation - Google Patents

Abstract

FIELD: medical chemistry.

SUBSTANCE: invention refers to granules, pills and to the method and installation of their production. During the process of making granules the powder is subject to low compacting force to receive compressed mass including the mixture of small particles and granules. Then small particles are separated from the granules by introducing small particles into the flow of gas. The direction of gas flow has a component flowing counter the direction of compressed mass flow.

EFFECT: increase of homogeneity and avalanche ability of granules.

36 cl, 20 dwg, 13 ex

Description

Technical field

The invention relates to granules and tablets, as well as to a method and apparatus for their preparation.

State of the art

Pills are one of the most commonly used forms for most medicines. This situation can be explained by the fact that this dosage form allows for accurate dosage of the active component of the drug composition. Moreover, the handling and packaging of these products is simpler, and the life and stability of these products are usually better than other formulations.

The same arguments explain the reason why tablets are often used as a medium in other applications, such as food products, including confectionery, fragrances or sweeteners, detergents, dyes, or phytosanitary products.

The granular granular mass, which is necessary for the manufacture of tablets, can be obtained using two main methods, wet granulation or dry granulation. Tablets can also be made using direct compression. Direct compression relates more to the tabletting process per se than to the preparation of the starting material.

In wet granulation, the components are usually mixed and granulated using a wet binder. The wet granules are then sieved, dried and, if necessary, crushed before pressing to obtain tablets. Wet granulation is widely used in the pharmaceutical industry, although it turned out to be a difficult method, mainly due to the fact that the liquids needed in the manufacturing process of granules and tablets often have a negative effect on the characteristics of active pharmaceutical ingredients (APIs) and / or a final product, such as a tablet.

Dry granulation is usually described as a method of controlled crushing of pre-compacted powders, compacted either by clumping or by passing material between two rolls with opposite rotation. More specifically, powdered components, which may contain very fine particles, are usually mixed prior to compaction to obtain solid preforms, which are then ground and sieved before the other ingredients are added and finally compressed to form tablets. Due to the fact that in the dry granulation method essentially no liquids are used, the problems associated with wet granulation are avoided. Although dry granulation in many cases seems to be the best way to obtain products, such as tablets containing APIs, it is used relatively little because of the difficulties in producing the required type of granules, as well as in controlling granular material in the manufacturing process. Known methods of dry granulation, as well as related known problems, are well described in scientific articles, such as the review article "Roll compaction / dry granulation: pharmaceutical applications" ("Rolling compaction / dry granulation: application in the pharmaceutical industry"), written by Peter Kleinebudde and published in European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) pp. 317-326.

Direct compression is generally considered the easiest and most economical way to make tablets. However, it can only be applied to materials that do not need to be granulated before tableting. Direct pressing requires only two principal stages, namely, mixing all the ingredients and pressing this mixture. However, direct compression is applicable only to a relatively small amount of substances, since the ingredients of the tablets often need to be processed using some kind of granulation technology in order to make them compressible and / or to improve their uniformity and flowability.

The pill component is usually described either as an excipient or as an active ingredient. The active ingredients usually have a pharmaceutical, chemical or nutritional effect, and they are present in the tablet only in the required amount to provide the desired effect. Excipients are inert ingredients that are included to facilitate the manufacture of dosage forms, or to coordinate release characteristics of the active ingredients, or for other purposes auxiliary to the goals of the active ingredients.

Excipients can be characterized according to their functions in the composition such as, for example, lubricants, glidants, fillers (or diluents), disintegrants, binders, flavors, sweeteners and coloring agents.

Lubricants are designed to improve the extraction of the pressed tablet from the mold of the tablet manufacturing equipment and to prevent adhesion to punches.

Glidants are added to improve the flowability of the powder. They are usually used in order to facilitate uniform and uniform filling of the mold with the mixture of components before pressing.

Fillers are inert ingredients, sometimes used as bulking agents in order to reduce the concentration of the active ingredient in the final formulation. Binders in many cases also act as fillers.

Baking powder can be added to the compositions to facilitate the disintegration of the tablets when they are placed in a liquid environment, and thus the release of the active ingredient. Disintegration properties are usually based on the ability of the disintegrant to swell in the presence of a liquid, such as water or gastric juice. This swelling destroys the continuity of the tablet structure and thus allows the various components to enter the solution or suspension.

Binders are used to bond the structure of the tablet. They have the ability to bind together other ingredients after applying sufficient pressing forces and contribute to the integrity of the tablets.

Finding the right excipients for specific APIs and finding the right manufacturing methods for the combination of excipients and APIs can take a lot of time, which can take a long time, even years, to delay the process of developing a pharmaceutical product, such as a tablet.

Methods of both dry and wet granulation, known from the prior art, can provide solid bridges between particles inside the granules, which may be undesirable, for example, because they subsequently lead to unsatisfactory tablet characteristics. Hard bridges can be caused by partial melting, hardening of binders or crystallization of solutes. Partial melting may occur, for example, when a high compaction force is used in dry granulation processes. When the pressure is removed during the compaction process, crystallization of the particles can occur, which binds the particles together. The introduction of hardening binders is common in pharmaceutical wet granulation, when the binder is included in the granulating solvent. The solvent forms liquid bridges, and the binder solidifies or crystallizes upon drying to form solid bridges between the particles. Examples of binders that can act in this way are polyvinylpyrrolidone, cellulose derivatives (e.g. carboxymethyl cellulose) and pregelatinized starch. Substances such as lactose, which can dissolve during wet granulation, can subsequently crystallize upon drying, acting as a hardening binder.

Electrostatic forces can also be important, as the cause of the powder sticking together and the initial formation of agglomerates, i.e. while stirring. In general, they do not contribute significantly to the final strength of the granules. However, the magnitude of the Van der Waals forces can be approximately four orders of magnitude higher than the electrostatic forces, and these forces can make a significant contribution to the strength of the granules, for example, those granules obtained by dry granulation. The magnitude of these forces increases with decreasing distance between the surfaces of the particles.

In addition to finding a practical method for manufacturing a pharmaceutical product, the validity of the manufacturing method is essential. Validity means that the method should ensure reliable receipt of an acceptable consistency and predicted yield each time the method is used. Wet granulation processes are very difficult to control in this regard. The wet granulation process is often quite sensitive to small changes in manufacturing conditions. For example, a change in the moisture content of starch during the manufacturing process after drying may result in a tablet that is too hygroscopic or has a reduced shelf life. When a pharmaceutical product is developed under laboratory conditions, the conditions can be adjusted quite simply. However, the conditions available in the environment during mass production are usually less precisely regulated, thus making the validity of the manufacturing method a difficult and time-consuming task. The same can be said about direct compression methods, where the quality of the final product depends on the physical properties of the API and excipients. A slight change in such properties can lead, for example, to delamination and flow problems.

Due to production problems and the validity of the method associated with wet granulation and direct compression methods, it is desirable, especially in the pharmaceutical industry, to use dry granulation methods when possible. However, in the dry granulation methods known from the prior art, granules are obtained which are rarely suitable for the tablet manufacturing process. Conflicting process parameters often lead to compromises when some properties of the resulting granular product may be good, but other required properties are insufficient or absent. For example, the flowability characteristics of the granules may be unsatisfactory, the inhomogeneity of the granules may cause delamination during production or destruction along the diagonal planes of the compressed tablets, or some of the granules may exhibit excessive hardness, all of which can make the tabletting process very difficult, slow and sometimes impossible. Moreover, bulk granules may be difficult to compress into tablets. Alternatively or additionally, the breakdown characteristics of the resulting tablets may not be optimal enough. Such problems are usually associated with the heterogeneity and structure of the granules of the granular mass obtained by means of a sealant. For example, the mass may have a too high percentage of fine particles, or some granules obtained by means of a compactor may be too dense for effective tableting.

It is also well known in the art that, to obtain uniform tablets, the volume of material to be tabletted must be uniform and must have good flow properties.

In prior art dry granulation methods, such as compaction in rolls, the resulting granular mass usually does not have uniform flowability, for example, due to the presence of relatively large (1-3 mm) and dense granules, along with very small (e.g. 1 -30 μm) particles. This can cause delamination, since large, usually dense and / or hard granules of the prior art move differently than small particles when the granular mass is moved in the process, for example, during tableting. Due to delamination, it is often difficult to guarantee acceptable tablets. For this reason, some known devices are used in the prior art, in which small particles, and sometimes also the largest particles, are separated from the remaining granules using a fractionating device such as a vibrating screen (set of vibrating screens). This method is usually complex and noisy and results in a relatively uniformly moving loose mass in which the granules are hard and difficult to compress into tablets. Moreover, the method of separating small particles from granules becomes very difficult if the material is sticky and the size of the sieve is not large enough. Typically, in this method, the sieve openings should have a minimum size of at least 500 microns.

Another problem that arises in the prior art dry granulation processes is the difficulty in preparing, at the development stage, a test granular mass that is typical of a granular mass in production. Thus, the compaction forces and other compaction parameters used on a laboratory scale can be very different from those used on an industrial scale. As a result of this, the properties, for example, the flowability of the granular mass during production, can be very different from the flowability of the mass, which was made in the experimental setup. One of the screening methods applicable on a laboratory scale is screening in an air stream. One conventional air sieve involves passing the powder through a grid with cells of a certain size in order to exclude particles below a certain size (the required granules are delayed above the grid cells, and unaccepted particles pass below). Air is passed through mesh cells to carry away fine particles. A problem with prior art air screens is that their throughput is insufficient for the industrial production of granular mass. Moreover, air sieves that rely on mesh size when separating unacceptable material often exclude suitable small granules from an acceptable granular mass when separating small particles from the mass. Moreover, brittle granules can be destroyed during the sieving process, when particles below a specified size seep through the sieve openings.

Patent Application WO 99/11261 describes granules obtained by dry granulation, which may include only APIs. The method described in the application uses a prior art air sieve to separate fine particles (particles and granules smaller than 150 or 125 μm) from granules comprising up to 100% API. When sieving, a sieve is used whose cell size is approximately equal to the maximum size of unacceptable particles, for example, 150 microns. It seems that the granules described are obtained using relatively high compaction forces, since the fraction of small particles (less than 125 microns) after compaction is not more than about 26% (see Table 1). After sieving in the method, a granular, uniform granular mass is obtained, which is believed to include solid granules and substantially free of granules and particles of less than 150 or 125 microns.

US Pat. No. 4,161,516 proposes a composition for treating air sickness using soft tablets or granules for administration by inhalation. The method of the patent is suitable for producing granules that are soft enough to disintegrate in a stream of air.

US Pat. No. 6,752,939 teaches a method and apparatus for predicting the suitability of a substance for dry granulation by compaction on rolls using small samples.

UK patent 1,558,153 describes a method for producing an organic coloring material from finely divided particles by compressing said finely divided particles to obtain a bound mass of material, grinding said bound mass of material and extracting granular material with a particle size of 100 to 1000 μm from said ground material. The smallest particles were removed by a stream of air.

Applicant has discovered an improved method for preparing granules and tablets. The method is applicable to a wide variety of substances in the form of a solid powder, for example, for APIs and excipients, as well as for non-pharmaceutical products, for example, products that are used in the chemical and food industries.

According to the present invention, there is provided a method for producing granules from a powder, in which a low compaction force is applied to the powder to obtain a compacted mass including a mixture of fine particles and granules, and small particles are separated from the granules by involving small particles in a gas stream.

This method usually further includes a step of collecting granules. As explained below, the method can usually be carried out in a continuous manner.

Preferably, the method is performed essentially in the absence of liquid.

A powder, for example, APIs and / or excipients suitable for the pharmaceutical industry, used in the granulation method of this invention typically includes fine particles. Moreover, the powder can usually have an average particle size of less than 100, 50 or 20 microns. Fine powder particles can usually have a minimum size of 2.5 or 10 microns and a maximum size of 150, 100 or 75 microns. The applicant believes that new ideas of the method described here can also be applied to the formation of granules from a powder in which the minimum particle size is smaller than the typical aforementioned minimum size, for example, it can be 0.001, 0.01 or 1 μm.

The average particle size can be measured, for example, using a set of sieves. In the case of very fine powders, microscopy can also be used to analyze particle sizes. The flowability of such powders is usually unsatisfactory, for example, for tabletting purposes. An exemplary method for determining satisfactory mass flowability is described in the detailed description of FIG. 9.

Therefore, “fine particles” or “fines” are individual particles, usually having an average size of less than 100, 50 or 20 μm and a maximum size of 150, 100 or 75 μm.

When several small particles (for example, 3, 5, 10 or more) agglomerate to form granules of a maximum size of 150, 100 or 75 μm, they are called small granules. Granules larger than the maximum size are called "acceptable granules." The granules that remain after entrainment by a gas stream of small particles and / or small granules are called “accepted granules”.

A low sealing force can be achieved, for example, by using a roller seal. The roller compactor can be connected to a possible screen for breaking the flakes or other device, for example, a vibrating or rotating mill, suitable for producing granules from a compacted material. A possible step of using a screen to grind flakes, or another device, if necessary, provides the preparation of material for separating small particles and / or small granules from other granules.

Thus, typically, a compaction force is applied to the powder through a process involving the use of a roller compactor to produce a densified powder tape that is crushed to produce granules, for example, by a device for grinding flakes. A device for grinding flakes or a similar device can determine the upper adjustable size of the granules, for example, by passing them through a screen. The size of the opening of the screen for grinding flakes can be, for example, 0.5 mm, 1 mm or 1.2 mm.

The low compaction force can be adjusted to a minimum value so that at least one, five, ten, or fifteen percent of the powder material is converted into acceptable granules during the compaction and / or fractionation steps, while the rest of the material remains as fine particles and / or small granules.

According to observations, if the compaction force used is too low, the granules adopted in the process may be too fragile, for example, for tabletting. Such granules may also be too large, for example, greater than 3 mm. Fragile granules may not have sufficient flowability or not be hard enough to handle, for example, when tabletting.

The lowest possible compaction force can be selected so that 75% or less, 70% or less, 65% or less, 50% or less, or 40% or less of the powder is compacted into acceptable granules, and the rest remains in the form of small particles and / or small granules. The maximum low seal force is typically up to 500%, 250%, or 150% of the minimum low seal force.

For example, the compaction force may be low enough so that 75 wt.% Or less of the powder is compacted to obtain acceptable granules having a particle size of more than 150 μm (and / or an average size of 100 μm or more), and the rest of the powder remains in the form of fine particles and / or small granules.

The maximum and minimum low compaction forces, of course, depend on the particular compaction device and powder used. Thus, for example, the minimum low compaction force can be selected so that it is the minimum possible compaction force of 15 kN, 20 kN, or 30 kN for the Berech Pharmapaktor L200 / 50P Hosokawa ™ Roller Seal (Osaka, Japan). The lowest possible sealing force can also be selected so that it is 80 kN or less, 70 kN or less, 60 kN or less or 45 kN or less for the Hepokawa ™ Top Pharmapaktor L200 / 50P Roller Seal.

Typically, a low compaction force is 60 kN or less, for example 45 kN or less. Typically, low compaction force is 16 kN or more.

The maximum low compaction force can also be adjusted so that substantially no solid bridges form in the granules of the resulting mass, for example, due to heating of the mass. Some sealing devices known in the art provide cooling means for the densified material in order to mitigate the heating problems resulting from the use of high sealing forces. When using the method and system of the present invention, these precautions are not necessary.

The seal force can be adjusted using a method suitable for the seal used, for example, by adjusting the feed rate to the seal.

The gas flow can be ensured by any suitable means, for example, an exhaust fan. The flow of gas, such as air, can be directed through the chamber for separation into fractions. A gas stream separates at least some fine particles and / or small granules from the mass, including acceptable granules, small granules and small particles. The separated fine particles and / or small granules involved in the gas stream can be moved from the fractionation chamber to a separation device, for example, a cyclone, in which the carrier gas is separated from the small particles and / or small granules. Small particles and / or small granules can then be returned to the system for immediate reprocessing (i.e., they are recycled for compaction) or they can be placed in a reprocessing container later on.

Thus, small particles and / or small granules are easily separated from suitable granules by means of an apparatus including fractionation means. Desirably, the fractionation means includes a fractionation chamber.

As discussed in more detail in the examples, the largest acceptable granules exiting from the fractionation chamber are usually larger than the largest granules entering the fractionation chamber. It is believed that the process by which small granules and / or small particles agglomerate with larger granules proceeds during the transportation of the material through the fractionation chamber.

Preferably, the flow direction of the gas stream has a component that is opposite with respect to the flow direction of the compacted mass as a whole and the granules received in particular. Typically, the direction of flow of the gas stream is substantially opposite (e.g., about 150-180 °) and preferably opposite to the direction of flow of the compacted mass.

The gas may be, for example, air (preferably dry air).

The fractionation means may include means for directing the gas flow to the fractionation means, means for driving the compacted mass into motion, and means for directing the removed fine particles and / or small granules involved in the gas stream from the fractionation means, for example, for reprocessing. The compacted mass can be set in motion simply by gravity and / or by mechanical means.

A number of fractionation means are known which may be suitable for use in the practice of the invention. For example, the fractionation means may include a movable device, for example, a rotating device, such as a cylinder (or cone), along the axis of which the compacted mass moves in a gas stream. The compacted mass can be moved under the action of gravity, or it can be facilitated by mechanical means, or by means of a device (for example, a cylinder). The rotary device may include at least one structure for guiding the compacted mass into the rotary device, for example, by providing a spiral structure. The spiral structure can be formed from channels or dividing walls that direct the movement of the compacted mass. The component of gravitational support or resistance can be provided by tilting the axis of the rotating device.

Advantageously, the fractionation means does not require passing the compacted mass through any sieve (such as a wire mesh). Sieves tend to break poorly compacted granules, therefore, eliminating the use of sieves allows you to save weakly compacted granules with their favorable properties, for example, for tableting. Moreover, the sieves are easily clogged, which interrupts the process, especially when it is carried out in a continuous manner. In addition, the actual size of the sieve lumen may vary during the period of operation due to temporary clogging.

The fractionation means may be provided with holes in which small particles and / or small granules are drawn. In one specific embodiment of the invention, the gas stream enters the rotary device along its axis (in the opposite direction to the movement of the compacted mass) and leaves the rotary device through openings (perforations) in the side walls of the rotary device.

As noted above, the fractionating means may include a movable device, for example a rotating device, for moving the compacted mass in the fractionating means. The mobile device may be provided with openings through which a gas stream flows in and out of the mobile device and into which small particles and / or small granules are drawn. The holes through which gas flows from the device can be significantly larger than unacceptable small particles, for example at least 50%, 100% or 150% of the average diameter of the received granules. In absolute terms, the holes may, for example, have a minimum size of about 250 microns, 500 microns or 750 microns or more. This helps prevent clogging of the holes even when relatively large volumes of small particles of possibly sticky material need to be separated from the compacted mass. In this sense, the mobile device is significantly different from the prior art air sieve, where the mesh size of the sieves should be about the same as the largest unacceptable particle. Instead of relying on the size of the cell when sifting, the fractionator according to the invention relies on the ability of the gas stream to remove fine particles from the moving compacted mass. The establishment of the size of acceptable granules is achieved by coordinating their gravity (together with other forces, for example, mechanical and centrifugal forces) with respect to the force of the gas flow.

Some of the small particles and / or small granules can agglomerate into other granules in a fractionating means and / or in a pneumatic conveying means due to individual or combined influence, for example, carrier gas flow, mechanical forces, attractive forces and electrostatic forces. Thus, in the method it is possible to obtain granules that are larger than those obtained by means of a screen for grinding flakes included in the system. In some embodiments, the degree of agglomeration of the compacted mass in the fractionation step can be significant.

The movement of the mass in the gas stream can be achieved, for example, by applying mechanical force, gravity, centrifugal force, or a combination thereof. In some embodiments, the mechanical displacement component in the fractionation means may not be required at all to take advantage of the present invention. In some embodiments, acceptable granules fall in a gas stream, for example, due to the influence of gravity, and unacceptable particles and granules move, at least partially, in the opposite direction of the gas stream.

Typically, the average residence time of the compacted mass inside the fractionator is at least 2 seconds, possibly even at least 5 seconds, although the desired fractionation effect (including any agglomerating effect) can also be achieved in a shorter time.

It should also be noted that the unacceptable part of the mass may also contain acceptable granules. By allowing some recycling of the acceptable granules, the overall installation can be made, for example, more efficient and easier to maintain, since clogging of the fractionation means can be more easily prevented. These unacceptable acceptable granules can be transported to the beginning of the granulation process along with other unacceptable material for reprocessing. For efficiency purposes, it is preferable that a maximum of 30, 45, 60, or 75% of the acceptable granules are recycled to the fines method. The inventors did not observe any harmful effect on the granular mass caused by recirculation. This is attributed to the application of low compaction force.

According to a further feature of the invention, there is provided an apparatus comprising compaction means and fractionation means adapted to separate fine particles and / or small granules from a compacted mass by involving small particles and / or small granules in a gas stream.

Thus, the installation according to the invention may differ in that said means of fractionation, for example, including a rotating device (see, for example (401) in the drawings), includes at least one outlet (see, for example (511) in drawings) through which said gas stream flows from said means, said hole being large enough to allow a granule having acceptable properties (e.g. flowability, tableability, size, especially size) to exit said th device.

The installation may further include a release agent (eg, cyclone) for separating the gas stream from particles removed from the compacted mass.

An additional specific aspect of the invention provides a dry granulation apparatus, characterized in that it includes a compaction means capable of generating a low compaction force and a fractionation means adapted to separate fine particles and / or small granules from the compacted mass by involving small particles and / or small granules into a gas stream. The installation may accordingly include a roller compactor to obtain a tape of compacted powder, which is then crushed to obtain granules. The specified installation may differ in that the said means of separation into fractions includes means for moving the specified compacted mass. Said means for moving said compacted mass may include means for moving said compacted mass using gravitational or mechanical means. An apparatus according to the invention may, for example, be characterized in that said fractionating means includes at least one structure (see, for example (403) in the drawings) for guiding said compacted mass inside said fractionating means.

The installation according to the invention may include means for providing a gas flow, where the direction of the gas stream has a component that is opposite to the direction of flow of the compacted mass (for example, the direction of flow of the gas stream is essentially opposite to the direction of flow of the compacted mass).

The apparatus according to the invention is usually provided with fractionation means, which includes a rotating device (for example, a cylinder or cone, in particular a cylinder), along the axis of which the compacted mass moves in the specified gas stream. The movement of the compacted mass along the axis of the rotating device can be facilitated by a spiral structure that guides the movement of the compacted mass. The fractionation means, for example, a rotating device, may be provided with holes in which small particles and / or small granules are drawn. When you want to obtain granules with an average size x, the holes can have a minimum size of 0.5x, or 1.0x, or even 1.5x. In absolute values, the openings may, for example, have a minimum size of 250 μm, 500 μm or 750 μm.

The invention also provides a fractionation device adapted to separate small particles and / or small granules from the compacted mass by involving small particles in a gas stream that includes a rotating device, such as a cylinder or cone, along whose axis the compacted mass moves in said stream gas, and the specified rotating device is made with holes in which small particles and / or small granules are involved.

In one embodiment, the fractionation device includes a fractionation chamber, within which an open cylinder (or cone) is mounted. An open cylinder (or cone) is rotatably mounted on rollers. The carrier gas is fed into the open cylinder (or cone). The shell of the cylinder (or cone) may be provided with openings through which small particles and / or small granules are drawn into the carrier gas. As described elsewhere in this document, the particulate and / or small granules involved can be collected for recycling.

In the method and installation according to the invention, pneumatic conveying can be used. Accordingly, the gas used to entrain the fine particles of the compacted mass is in fluid communication with the carrier gas used to transport materials during continuous operation.

Thus, it is preferable that the powder for compaction is transported from the reservoir to the means of applying compaction force by means including the use of a pneumatic conveyor.

During pneumatic transport, a device, for example, a cyclone, can be used to separate the carrier gas from small particles. The device may, for example, be capable of continuous operation with an approximately uniform gas flow rate, in the sense that the carrier gas stream used in the fractionation process is not disturbed by pressure changes, for example, shock waves, such as those required for keeping open filters of various types.

“Continuous operation” in this context means the ability to carry out work without maintenance or other process shutdowns for at least one hour, eight hours or 24 hours.

One aspect of the invention is a dry granulated mass containing granules which can be obtained according to the method of the invention.

The invention also provides a granular mass in which the granules can have an average size of more than 50, 100, 200 or 500 μm, a maximum granule size of 3, 2 or 1 mm and good flowability. The mass may alternatively or additionally have at least one, two, three or four of the following properties selected from the essentially absence of solid bridges between particles inside the granule, good uniformity, porous structure of the granules, the presence of a significant proportion of small particles and / or small granules in weight (usually associated with other granules), good compressibility and tableting. Preferably, the granules have an average size of more than 100 μm and a maximum size of 3 mm.

Further, without regard to any theory, the applicant believes that the product of the method according to the invention is subject to triboelectric effects caused by the passage of the powder through the system. In the prior art, it is assumed that small particles may tend to acquire a negative charge, while large particles acquire a positive charge (or at least a smaller negative charge) (see, for example, the article “Generation of bipolar electric fields during industrial handling of powders "(Ion. I. Inculet et al., Chemical Engineering Science, 61 (2006), pp. 249-2253), for example, when transported by gas flow or other movement in a gas stream. Thus, according to one contemplated embodiment of the invention, a granular mass obtained by dry granulation is provided, characterized in that it contains granules having typically an average size of from 50 μm to 3 mm (e.g., from 100 μm to 3 mm), consisting of (a ) a dense core containing fine particles of material bound by van der Waals forces, and (b) a coating layer containing fine particles and / or small granules of said material associated with said dense middle by electrostatic forces. According to another contemplated embodiment of the invention, a granular mass obtained by dry granulation is provided, characterized in that it contains granules having an average size of from 50 μm to 3 mm (e.g., from 100 μm to 3 mm), consisting of (a) a dense core, containing fine particles of material bound by van der Waals forces, and (b) a porous coating layer containing fine particles and / or small granules of said material. In one embodiment, the coating layer (b) contains mainly, for example, 70, 80 or 90% of fine particles, and the rest is made up of small granules. In another embodiment, the coating layer (b) contains mainly, for example, 70, 80 or 90%, small granules, and the rest is made up of small particles.

Preferably, the dense core is substantially free of solid bridges.

Such a granular mass obtained by dry granulation may also differ in that the average particle size of the material is 1-100 μm, the average size of the dense core is 50-3000 μm, for example 100-3000 μm, and the ratio of the average size of small particles and / or small granules of the material of the coating layer to the average size of the dense core is at least 1:10, for example at least 1:30.

The most desirable characteristics of the granular mass are usually good flowability, good tableting, good uniformity, the porous structure of the granules, a significant proportion of small granules in the mass and a significant absence of small particles in the mass.

To analyze the particle size of the granular mass, you can use a set of, for example, four sieves, where the mesh sizes of the sieves are, for example, 850 μm, 500 μm, 250 μm and 106 μm.

The average granule size of the material adopted by the means of separation into fractions can be calculated as the geometric mean diameter of the holes of two adjacent sieves in the kit.

d _i = (d _u · d _o ) ^1/2 ,

where d _i is the diameter of the i-th sieve in the kit;

d _u is the diameter of the hole through which the particles will pass (sieve, subsequent i-th);

d _o - the diameter of the hole through which the particles will not pass (i-th sieve).

Since it is practically impossible to calculate each particle separately and calculate the average, the average particle size can be calculated on the basis of mass. This can be done, for example, using the following equation:

d _gw = log ^-1 [Σ (W _i logd _i ) / ΣW _i ].

The standard deviation can be calculated as follows:

S _gw = log ^-1 [ΣW _i (log d _i -log d _gw ) ² / ΣW _i ] ^0.5 .

A more detailed description of the size analysis method shown here as an example can be found in "Scott Baker and Tim Herrman, Evaluating Particle Size, Kansas State University, May 2002".

You must take into account that when the particle size of the granular mass is analyzed using the above method, at least some of the particles / small granules of the coating layer can be separated from the dense core.

The flow characteristics, for example, good flowability, can be determined using an open cone having a circular hole at the narrower end of the cone, for example, a filter funnel. One set of such cones and the associated test method are described in more detail in connection with FIG. 9.

Essentially the absence of solid bridges in the structure of the granule means, for example, a structure in which on average less than 30% or 10% of the particles of the granule are held together by solid bridges. The presence of solid bridges in the structure of the granule can be analyzed, for example, using scanning electron microscopy. With such a device, it is possible to detect individual small particles in the granular structure, as well as visible solid bridges, such as crystallized structures between the particles of the granule.

Good uniformity in this context may mean, for example, a granular mass consisting of granules whose standard deviation from the average granule size is less than 2.5; less than 2.25 or less than 2.0. Further, the applicant believes that the homogeneous characteristics of the granular mass according to the embodiments of the present invention can be achieved, at least in part, due to the porous structure of the granules. Due to the uniform characteristics of the mass, it can be transported during the manufacturing process without any significant delamination of the material. In addition, good uniformity of the granular mass can contribute to good tabletability of the mass, for example, as demonstrated by the lower susceptibility of the pressed billet to destruction along diagonal planes.

The structure of the received granules, and especially the coating layer, can be generally porous, i.e. dense granules may be substantially absent in the granular mass. It is believed that the core of the granule is porous due to the use of low compaction force. The porous structure of the granules can alternatively or additionally mean, for example, that pores and / or loose small granules and / or small particles with a size of at least 1, 2 or 5 μm and less than 150, 100 or 50 μm can be observed on the surface of the granule . For example, images of granules having a porous structure, see Fig.2d, 2e and 2f.

Essentially the absence of dense granules means that less than 20 or 10% wt. the resulting mass are dense granules. A dense granule is, for example, a granule whose surface looks like a dense, non-porous surface (see, for example, Fig. 2c).

The granular mass may also include a significant proportion of small granules and / or small particles, possibly forming a coating layer on large granules, which are freely attached, for example, by electrostatic forces. A significant proportion of small granules and / or small particles may be more than 2%, 5% or 10% wt. from the total mass of the granulate.

The presence of small, preferably porous granules and / or small particles can make a positive contribution, for example, to the flowability and compressibility of the granular mass. This can lead, for example, to an improved tensile strength and / or faster disintegration of a tablet compressed from a granular mass. Unexpectedly, and in contradiction to the one described in the prior art, for example, in W099 / 11261, it was found that a significant proportion of small granules and / or small particles in the granular mass according to the invention, as it turned out, does not generally affect the flowability of the granular mass in any significant negative way.

The applicant also found that in at least some cases, if the granules obtained by the method according to the invention are taken, and again a fraction of the starting material consisting of small particles is added (for example, up to 15% of the small particles are again added to the granular mass, which may already have , for example, 20% of fine particles and / or small granules, for example, as in the mass of “Example 3 flowability”), the uniformity, flowability and tableting of the granular mass does not deteriorate significantly. The added fine particles are likely to be embedded in the porous surface of the granules formed by the method of the invention. Thus, the applicant believes that it is possible to use granules according to some embodiments of the invention as “carrier granules” that can absorb, for example, up to 10%, 20%, 30% or more of small particles and / or small granules, including the same or another material than the material of the carrier granules. The flowability of such a mixture can be excellent, very good or good.

It is believed that the granular mass has good compressibility due to the fact that at least the surface of the granules is porous. The compressibility of the granular mass according to the invention may be good, i.e. it can have a Hausner ratio of more than 1.15; 1.20 or 1.25. The low compaction force of the present invention can be selected so that the compressibility determined from the Hausner index remains at a good level.

The Hausner index can be calculated using the formula p _tap / p _bulk , where p _tap represents the bulk density of the granular mass with utrus and p _bulk represents the bulk density of the granular mass without utrus. Bulk density can be measured by filling 50 mg of the granular mass into a glass cylinder (for example, model 250: 2 ml manufactured by FORTUNA) having an internal diameter of 3.8 mm. After filling the mass into the cylinder, the mass volume is determined on a scale applied to the glass cylinder, and the bulk density of the mass is calculated without trimming. To measure the bulk density with an utrusa, the glass cylinder is hit 100 times on the upper surface of the table using a force comparable to a drop from a height of 5 cm. The mass volume after utrusi is observed on a scale applied to the glass cylinder, and the bulk density after the utrusi is calculated.

Unexpectedly, and in contradiction to the one described in the prior art, for example, in WO 99/11261, it was found that the compressibility of the granular mass according to the invention did not have any negative effect on the flowability of the granular mass. For example, the granular mass according to an embodiment of the invention with a Hausner index above 1.25 usually shows very good or excellent flowability characteristics.

Pourable granules with good flowability are usually required in the pharmaceutical industry, for example, because improved tablets can be obtained from porous granules. Such tablets can, for example, disintegrate much faster than tablets made from dense granules. Moreover, tablets compressed from porous granules often show greater tensile strength than tablets pressed from dense granules. High tensile strength is often required since such tablets are more easily packaged and transported than fragile tablets.

The granular mass can be tabletted so that using conventional tabletting technology, for example, using the tabletting forces provided by widely used tabletting machines, it is possible to produce tablets. having a tensile strength of at least 5 N, 10 N or 15 N. The tensile strength can be measured, for example, using a measuring device manufactured by MECMESIN ™ (Mecmesin Limited, West Sussex, UK), model BFG200N.

The granular mass may include at least one API and / or at least one excipient used in pharmaceutical products. In one embodiment, the granular mass comprises (for example, consists of) at least one (eg, one) API. In another embodiment, the granular mass comprises at least one (eg, one) API and at least one (eg, one) excipient.

Thus, the invention also provides a method for preparing a tablet, comprising compressing a granular mass obtained by dry granulation according to the invention, possibly mixed with one or more additional excipients. Said one or more additional excipients usually include a lubricant, for example, magnesium stearate. A tablet that can be obtained by this method is another aspect of the invention.

According to another feature of the invention, provide a tablet comprising granules obtained by dry granulation. A tablet is characterized in that it may essentially not contain solid bridges linking the particles inside the granules forming the tablet. Alternatively or additionally, a tablet may possess at least two or three of the following properties: high tensile strength, high drug content, low amount of lubricant, rapid disintegration, and storage stability.

Storage stability may mean, for example, that the weight gain of a tablet compared to a new tablet is less than 2.0%, 1.5% or 1.0% after the tablet has been stored for four months at a temperature of 40 ° C and relative humidity of 75%.

A high drug content means that the tablet may include, for example, at least 40%, 60% or 80% of the API total weight of the tablet.

Rapid disintegration can be less than 600, 120 or 30 seconds when the tablet is placed in water at a temperature approximately equal to the temperature of the human body (i.e. 37 ° C).

As can be seen from the examples, tablets according to the invention, which have high tensile strength, can, however, be capable of rapid disintegration in water.

The high tensile strength of the tablet may be more than 100 N, 60 N, 30 N or 15 N, for example, as determined by the MECMESIN ™ BFG200N device.

A low amount of lubricant may be less than 1.0%, 0.5%, 0.3% or 0.2% by weight of the tablet. It is known in the art that a lubricant such as magnesium stearate often has a negative effect on tensile strength, disintegration and / or tablet dissolution time. When mixing a lubricant with granules of the prior art, the lubricant may, for example, tend to form a film around the (dense) granules. The film may prevent proper bonding between the granules during tabletting. (See, for example, the article "A coherent matrix model for the consolidation and compaction of an excipient with magnesium stearate" by K. A. Rietma et al., International Journal of Pharmaceutics, 97 (1993), pp. 195-203). The use of a small amount of the lubricant with granules of the present invention can thus make a positive contribution to the tensile strength and disintegration of the tablets. The applicant suggests that a possible soft and porous surface of the granules of the invention can prevent the formation of such films due to the fact that the granules can have a larger, more uneven surface capable of associating with a lubricant. Thus, the properties of the resulting tablets can be further improved.

The lubricant can be essentially distributed on the porous surface of the granules of the tablets. The lubricant can, for example, be placed predominantly on the surface and in the pores of the surface of the granules forming the tablet, while the lubricant is not present, or is present in a small amount, inside the core of the granule. The lubricant can be distributed, for example, so that more than 90, 80 or 70% of the lubricant is placed on the cross-sectional area (cut surface), which is less than 10, 20 or 30% of the total cross-sectional area of the tablet. The location of the lubricant particles on the cross-sectional area of the tablet can be observed using, for example, a system including scanning electron microscopy and additional equipment capable of recognizing in particular particles including a lubricant.

The tablet may preferably have a substantially low percentage of liquids with hydrogen bonds, for example water.

Preferably, the tablet has a substantially low percentage of liquid and / or hydrogen bonds, the lubricant being not uniformly distributed in the tablet and the tablet additionally having at least two of the following properties: quick disintegration, high tensile strength, high drug content and low amount of lubricant .

A tablet of the invention may include an excipient that includes starch obtained by dry granulation. For example, it may include an excipient, which includes up to 60% of the starch obtained by dry granulation.

The granular mass or tablet of the present invention may typically include at least 1, 5 or 10% (wt.) And at most 100, 95, 90, 80 or 70% of at least one active pharmaceutical ingredient. In some embodiments, said powder comprises at least 60% of the active pharmaceutical ingredient, for example at least 80%. The granular mass or tablet may further include at least 5, 10, 20 or 30% (wt.) And at most 99, 95 or 90% of at least one excipient, for example, a long chain polymer, for example, starch or cellulose.

In order to control the disintegration and dissolution time of the tablets of the present invention, up to 90, 70 or 50% (wt.) Metolose or hypromellose (hydroxypropyl methylcellulose) can be added to the formulation. The dissolution time of such a tablet may be at least 1, 4, 8 or 12 hours in the digestive system.

The dissolution curve of a composition including, for example, hypromellose may be, for example, such that after about 2 hours, about 12% to about 60% of the API is released, after about 4 hours, about 25% to about 80% of the API is released, after about About 8% to about 100% of the API is released in 8 hours; after about 12 hours, more than 75% of the API is released.

To achieve rapid disintegration of the tablet, which includes at least 5, 20 or 30% (wt.) Of at least one active pharmaceutical ingredient, the tablet may further include at least 1, 3 or 5% wt. and a maximum of 7, 10 or 20% (wt.) baking powder. In some embodiments, the percentage of disintegrant in the tablet may also be higher than 20%. The baking powder may be, for example, any starch or carboxymethyl cellulose (CMC, for example, Nymcel ™), or a combination thereof. The granular mass or tablet may also include a minimum of 1.5 or 10% and a maximum of 60, 80 or 94% (wt.) Filler (diluent), for example, microcrystalline cellulose. API, baking powder and filler can be granulated together or separately, using the method of the present invention.

To improve the taste of, for example, a fast disintegrating tablet (tablet disintegrating in the mouth), up to 50, 70 or 90% of a sweetener, for example, xylitol, can be included in the tablet. If necessary, the sweetener can be granulated using an embodiment of the method of the present invention. In addition, the sweetener can be granulated separately or together with at least one component (API or excipient) of the composition. Applicants have found that with at least some APIs, the use of a separately granulated sweetener (xylitol) in a tablet can lead to a shorter release time compared to a tablet in which the sweetener is granulated together with other components.

The tablet of the invention may have good uniformity of composition. For example, the standard deviation of tablet weight may be less than 3.0%, 2.0%, or 1.0% of the average tablet weight.

The granulation method and apparatus according to the invention can be used for various purposes in the pharmaceutical, chemical and food industries. The method and installation use a low compaction force and a gas stream to form granules with the desired properties. The compaction force can be selected so as to substantially avoid the occurrence of solid bridges in the compaction step. The method and installation are adapted for the careful processing of the obtained granules, avoiding their destruction, in order to separate fine particles and / or small granules from acceptable granules and, possibly, recycle unacceptable material for reprocessing in the system. The installation and method can be made easily customizable, adjustable and more or less continuously operating.

The size distribution and / or flowability of the granules obtained by the installation can be analyzed in real time and the distribution of granule sizes can be selected based on this analysis. For example, the screen for grinding flakes (see Figa and 1b below) may be such that the size of the holes of the sieve used for grinding flakes can be changed using any means of regulation. Another tunable parameter is usually the gas flow rate in the fractionating device.

The method can be made economical, since it allows the reprocessing of unaccepted material with virtually no waste and it can be adapted to provide fast processing of a large amount of material. The installation of the present invention can be made easily cleanable and assembled, and the method can be made stable and predictable, thereby making it easily adjustable.

For example, due to the uniformity and / or flowability of the resulting granules, separation problems can be avoided. The method of the present invention can be used both in small-scale applications and in large-scale applications. Thus, when a product, such as a granule or tablet containing APIs, is successfully developed in the laboratory, the time required to set up a valid large-scale production process can be short.

Since using the method and installation of this system it is possible to granulate a variety of powders, including powders that are 100% API, it is possible to obtain a granular mass from individual substances in separate granulation processes and mix the resulting granules after their individual granulation. Granulating the APIs and excipients individually before mixing may be advantageous, for example, when the raw materials have very different particle sizes.

Various types of end products can be made from the granular mass, including tablets, oral suspensions and capsules.

According to the invention, a method for manufacturing a tablet is also provided, comprising tabletting granules according to the invention or granules made using the method according to the invention.

It was found that the method of the present invention can be used to obtain granules from a wide variety of powder substances used in the pharmaceutical industry.

Thus, the method of the present invention can be used to obtain granules and tablets according to the invention from a material comprising APIs of one or many classes of APIs, which classes include, for example, antipyretic drugs, analgesics, anti-inflammatory drugs, hypnotics, anti-drowsiness drugs, antacids , digestive, cardiotonic, antiarrhythmic, antihypertensive, vasodilator, diuretics, antiulcer drugs, carmin drugs, therapeutic agents for osteoporosis, cough suppressants, expectorants, anti-asthma drugs, fungicides, urinary aids, wellness products, vitamins and other oral drugs. An API can be used alone, or two or more APIs can be used in combination.

The method of the present invention can also be used to obtain granules and tablets according to the invention from a material comprising specific APIs, for example, paracetamol, acebutolol, metformin, fluoxetine, aspirin, aspirin-aluminum, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, isotypendiline, , diphenhydramine, dipheterol, triprolidine, tripelennamine, tonsilamine, phenethazine, methyldazine, diphenhydramine salicylate, carbinoxamine diphenyl disulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theoc atm, mebhydrolin napadizilat, prometazinmetilena disalicylate, carbinoxamine maleate, chlorpheniramine dl-maleate, chlorophenylamine d-maleate, difeterola phosphate alloklamid, kloperastin, pentoksiverin (carbetapentane) tipepidin, dextromethorphan hydrobromide, dextromethorphan fenolftalinat, tipepidina gibenzat, kloperastina fendizoat, codeine phosphate, dihydrocodeine phosphate, noscapine, dl-methylephedrine saccharin salt, potassium guaiacol sulfonate, guaifenesin, caffeine, anhydrous caffeine, vitamin B1 and its derivatives, vitamin B2 and its derivatives, vitamin HC and its derivatives, hesperidine and its derivatives and its salts, vitamin B6 and its derivatives, and nicotinamide, calcium pantothenate, aminoacetate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, aluminum glycinate, product of the co-precipitation of hydroxide / bicarbonate aluminum, co-precipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate, co-precipitation product of magnesium hydroxide / potassium aluminum sulfate, magnesium carbonate, magnesium aluminomethasilicate, ranitidine, cimetidine, famo thidine, naproxen, diclofenac, piroxicam, azulene, indomethacin, ketoprofen, ibuprofen, diphenidol, promethazine, meclizine, dimenhydrinate, phenetazine tannate, diphenhydramine fumarate, scopolamine hydrobromide, methylphenylbromide methyl benzene, methyl dimethylbromide, methyl dimethylbromide, methyl diphenhydramine dimethylbromide , belladonna extract, isopropamide iodide, papaverine, aminobenzoic acid, cesium oxalate, aminophylline, diprofillin, theophylline, isosorbide dinitrate, ephedrine, cephalexin, ampicillin, sucralfate, allyliso propylacetylurea, bromvalerylurea, and, where appropriate, the (other) pharmaceutically acceptable acid or base addition salts thereof (eg, common salts) and other such pharmaceutically active ingredients described in European Pharmacopoeia 3rd Edition, and one, two or more of them combined.

The method of the present invention can also be used to obtain granules and tablets according to the invention from a material comprising solid APIs which may be slightly soluble in water, such as, for example, antipyretic painkillers such as benzoic acid, quinine, calcium gluconate, dimercaprol, sulfamine, theobromine, riboflavin, mefenesin, phenobarbital, thioacetasone, quercetin, rutin, salicylic acid, pyrabital, irgapirin, digitoxin, griseofulvin, phenacetin, a medicine for the nervous system, sedative nar catarrhal substances, muscle relaxant, antihypertensive agent, antihistamines, antibiotics such as acetylspiramycin, erythromycin, kitasamycin, chloramphenicol, nystatin, colistin sulfate, steroid hormones, such as methyltestosterone, progesterone, estradiol benzoate, ethylene acetone estradiol, prednisone, non-steroidal vitelline hormones such as dienestrol, diethylstilbestrol, chlorotrianisene, other lipid-soluble vitamins, and where appropriate, (others) are pharmaceutically mlemye their addition salts with an acid or base (e.g., commonly used salts), and other such pharmaceutically active ingredients described in the European Pharmacopoeia, 3rd edition, and one, two or more of them in combination.

The active pharmaceutical ingredient can, for example, be selected from acebutolol · HCl, fluoxetine · HCl, paracetamol, sodium valproate, ketoprofen and metformin · HCl.

The method of the present invention can also be used to obtain granules and tablets according to the invention from a material comprising excipients or other ingredients applicable, for example, in the pharmaceutical industry, such as, for example, L-aspartic acid, wheat gluten powder, gum arabic powder, alginic acid , alginate, alpha starch, ethyl cellulose, casein, fructose, dry yeast, dried aluminum hydroxide gel, agar, xylitol, citric acid, glycerin, sodium gluconate, L-glutamine, clay, croscarmellose on ria, Nymcel ™, sodium carboxymethyl cellulose, crospovidone, calcium silicate, cinnamon powder, crystalline sodium carmellose cellulose, synthetic aluminum silicate, wheat starch, rice starch, potassium acetate, cellulose acetate phthalate, dihydroxyaluminyl-2-dimethyl-2-dimethyl-4-di-methyl-di-methyl , dimethylpolysiloxane, tartaric acid, potassium hydrotartrate, magnesium hydroxide, calcium stearate, magnesium stearate, purified shellac, purified sucrose, D-sorbitol, skim milk powder, talc, low substitution hydroxypropyl cellulose, dex rin, powdered tragacanth, calcium lactate, lactose, sucrose, potato starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, glucose, partially pregelatinized starch, pullulan, powdered cellulose, pectin, polyvinyl pyrrolidone, maltitol phosphate, maltitol phosphate, maltolitol, calcium maltolitol, maltolitol, maltoltol anhydrous calcium phosphate, magnesium aluminum metasilicate, methyl cellulose, aluminum monostearate, glycerol monostearate, sorbitan monostearate, medical charcoal, granular grain starch, dl apple cider slots and possibly other substances classified as excipients in Arthur H. Kibbe, Handbook of Pharmaceutical Excipients, 3rd edition, and one, two or more of them in combination.

The method of the present invention can also be used to obtain granules and tablets according to the invention from a material comprising disintegrants, such as, for example, carboxymethyl cellulose, Nymcel ™, sodium carboxymethyl cellulose, croscarmellose sodium, cellulose such as low substitution hydroxypropyl cellulose, such as starch, such as starch, such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, potato starch, corn starch, partially pregelatinized starch and other substances, classi cited as disintegrants in Arthur H. Kibbe, Handbook of Pharmaceutical Excipients, 3rd edition, and one, two or more of them in combination.

The method of the present invention can also be used to obtain granules and tablets according to the invention from a material comprising binders, such as, for example, synthetic polymers such as crospovidone; saccharides such as sucrose, glucose, lactose and fructose; sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol; water soluble polysaccharides, such as celluloses, such as crystalline cellulose, microcrystalline cellulose, powder cellulose, hydroxypropyl cellulose and methyl cellulose; starches, synthetic polymers such as polyvinylpyrrolidone; inorganic compounds such as calcium carbonate and other substances classified as binders in Arthur H. Kibbe, Handbook of Pharmaceutical Excipients, 3rd edition, and one, two or more of them in combination.

Examples of thinners include silicon compounds, such as silica hydrate, light silica, and other substances classified as thinners in Arthur H. Kibbe, Handbook of Pharmaceutical Excipients, 3rd edition, and one, two or more thereof in combination.

According to another aspect of the invention, a granular mass is provided, characterized in that it can be tabletted and has good flowability and comprises at least 10% of at least one of the following pharmaceutical ingredients:

- acebutolol · HCl,

- fluoxetine · HCl,

- paracetamol,

- sodium valproate,

- ketoprofen and

- metformin · HCl.

According to another aspect of the invention, provide a tablet, characterized in that the tensile strength of the tablet is at least 10 N and the tablet is made from granules obtained by dry granulation, including at least 10% wt. at least one of the following active pharmaceutical ingredients:

- acebutolol · HCl,

- fluoxetine · HCl,

- paracetamol,

- sodium valproate,

- ketoprofen and

- metformin · HCl.

According to another aspect of the invention, there is provided a tablet formed by compressing a dry granulated mass comprising 60% or more (e.g. 70%, or 80% or more) of an active pharmaceutical ingredient selected from paracetamol, metformin · HCl, acebutolol · HCl and sodium valproate . The rest of the composition of the mass obtained by dry granulation may, for example, be one or more disintegrants selected from starch, cellulose and cellulose derivatives. According to another aspect of the invention, there is provided a tablet formed by compressing a dry granulated mass comprising (1) granules comprising 80% or more (e.g. 90% or more, e.g. 100%) of an active pharmaceutical ingredient selected from paracetamol, metformin HCl, acebutolol · HCl and sodium valproate, and (2) granules comprising one or more disintegrants selected from starch, cellulose and cellulose derivatives. In any case, you can additionally mix the lubricant with the mass obtained by dry granulation before pressing it to obtain tablets.

In some embodiments, the tablets disintegrate in water at a temperature approximately equal to body temperature, i.e. 37 ° C in less than 60 seconds. For rapidly disintegrating tablets, the API content preferably does not exceed 95% of the composition of the tablet, and the composition contains at least 2% of a disintegrant. The tablets, respectively, have tensile strengths of more than 40 N. In one embodiment, the tablets may include xylitol in an amount of 90% or less.

Some embodiments of the invention are described herein, and additional uses and modifications of the invention will be apparent to those of ordinary skill in the art.

Brief Description of the Drawings

The invention is further illustrated, but in no way limited by references to the accompanying drawings, in which:

on figa and fig.1b shows as an example the installation according to one of the embodiments of the invention,

on figa shows the use of a roller seal according to one of the embodiments of the invention,

2b shows the use of a roller compactor, with which both impractical dense granules (according to the prior art) and the required porous granules are obtained,

on figs shows an example of a granule obtained by the method of the prior art,

2d shows an example of a granule according to one embodiment of the invention,

2e shows another example of granules according to one embodiment of the invention,

Fig.2f shows another example of granules according to one embodiment of the invention,

Fig.2g illustrates an example of the formation of a granular mass according to one embodiment of the present invention,

on fig.2h shows a diagram of the distribution of particle sizes for the materials shown in fig.2g,

Fig. 2i shows surface images of granules obtained using various low compaction forces according to embodiments of the present invention,

figure 3 shows as an example, a device for fractionation according to one embodiment of the invention,

figure 4 shows as an example a device for fractionation, which contains an additional rotating device used according to an embodiment of the invention,

5a and 5b show two alternative, exemplary cylindrical parts that can be used in the fractionation device shown in FIG. 4,

5c shows, by way of example, a perforated steel sheet that can be used as part of a rotary device according to one embodiment of the present invention,

FIG. 6 shows, by way of example, a dual-filter design for providing continuous operation of a system according to one embodiment of the present invention,

7 shows as an example the layout for monitoring and regulating the characteristics of the received granules in real time,

Fig. 8 shows, by way of example, an apparatus for mixing granular masses of substances densified individually,

figure 9 shows as an example a device for determining the flowability of a powder or granular mass.

Detailed Description of Drawings

Installation 100 (Figa and 1b) according to one of the embodiments of the invention includes a sealing device with which to compact the powder material to obtain granules, and a device for separation into fractions, with which at least some amount of fine particles and / or small granules from acceptable granules. Two different embodiments of the fractionation device are shown in FIGS. 1a and 1b. The fractionation device 112 of FIG. 1 a is shown in more detail in FIG. 3. The fractionation device 112 of FIG. 1b is shown in more detail in FIG. 4. The apparatus shown in FIGS. 1a and 1b includes a feed container 101 with raw material into which a material for granulation is supplied. The feed container is connected to a pneumatic conveying pipe 102, into which material enters through a feed valve 103. The pipes of the pneumatic conveying system have a diameter of about 47 mm and can be made, for example, of some suitable plastic material, for example polyethylene. The feed valve may be a so-called star-shaped flap valve. This type of valve is manufactured at Italian pharmaceutical device manufacturer CO.RA ™ (Lucca, Italy). During operation, the closing element of the valve can be rotated 180 ° alternately in any direction, as a result of which the deposition of powder substance in the container can be avoided. Other equipment provided for the continuous loading of the powdered substance, such as chamber feeders, can also be used.

The pressure of the air flowing inside the conveyor 102 can be adjusted so that it is lower than the ambient pressure. This can be achieved, for example, by using an exhaust fan 104. The exhaust fan is a Mink MM 1202 AV model manufactured by BUSH ™ (Malburg, Germany). The fan can function, for example, at 1860 rpm. The make-up carrier gas can be supplied via connection 105. The material supplied from the supply container is transported through a conveyor 102 to a separating device 106, in which small unacceptable particles and a new feed from the container 101 are separated from the carrier gas. The fan can be equipped with filters (shown in Fig.6) located next to the separating device. The device may be capable of continuous operation. One such device is a cyclone. After the separation step, the separated powder falls into the intermediate vessel 107.

Vessel 107 can be mounted on load cells 108 to measure mass of material. The intermediate vessel 107 is equipped with a valve 109, which may be of the same type as the valve of the supply container 103. From the intermediate vessel 107, the powder is transported to a sealing device, for example, to a roller seal 110 to obtain a tape of compacted material, which then passes into the screen 111 grinding flakes (flake crushing screen), where they create granules by breaking the tape. In the context of this invention, compaction is considered to be a process step in which granules intended to be fractionated are obtained, regardless of whether separation screen or grinding device 111 is used. The compaction force of the seal 110 can be adjusted by, for example, changing the feed rate of the powdered substance, the speed of rotation of the rolls of the roller seal, the pressure applied to the rolls of the sealing device, and / or the thickness of the resulting tape. The sealing force applied by the sealant can be adjusted to a low level in order to achieve the desired properties of the compacted mass, for example, the porosity of the resulting granules and / or the fraction of small particles and / or small granules. The compactor and screen for grinding flakes are devices well known to a person skilled in the art. After passing the sealing device and the device for grinding flakes, the material is partially in the form of granules, however, part of the material still remains in the form of fine particles and / or small granules. The maximum size of the granules, as well as the average size of the granules, can be influenced, for example, by the size of the mesh of the sieve for grinding flakes. It should be noted, however, that the granule size may increase as a result of agglomeration in the process steps, such as fractionation and / or transportation.

In some embodiments (not shown in the figures), the installation 100 may include more than one sealing device, for example, a roller seal, to improve, for example, productivity and / or the ability of the installation to be processed continuously. Sealing devices may require some periodic maintenance stops, such as cleaning. Installation 100 can operate continuously, even if one of the sealing devices is under maintenance.

The product of the above steps, which contains fine particles and porous granules and which may have a static electric charge (for example, by friction electrification), transport chamber 112 for fractionation. It may comprise one or two star-shaped flap valves between the sealing device and the fractionation device to control the flow of the densified material supplied to the fractionation device. In the fractionating device, the granular mass is divided into a received fraction and an unaccepted fraction based on how different carrier particles are affected by the flow of carrier gas that flows in the fractionating device. The non-received fraction passes with the flow of the supplied carrier gas to the feed conveyor 102 for reprocessing, and the received fraction is sent to the product container 113. By this means, the obtained granules are carefully processed and a relatively large volume of material, including mainly small particles and / or small granules, is removed from the mass.

The operation of the fractionation chamber 112 is described in more detail with reference to FIGS. 3-6. There are many possible alternative fractionation devices.

In the embodiment shown in FIGS. 1a and 1b, load sensors 108 are attached to the container 107. Such sensors and other measuring devices can also be placed in other containers and system components. Not all possible measuring devices are shown in the drawings. For example, the pneumatic conveyor, if required, can be equipped with at least one differential pressure sensor 114, information from which can be used to regulate the operation of the installation.

The present invention can also be carried out in a batchwise manner in which an unaccepted fraction is not returned directly to the system using a conveyor 102, but is fed into a container with unaccepted material. Such a system is not described in detail, however, its design and use are well understood by a person skilled in the art.

The installation can be automated by transmitting information received from various sensors, for example, differential pressure sensors 114, load sensors 108 and valves 103, as well as information related to rotational speed and engine loads, to the control unit and by applying the appropriate control logic and control loops in a manner known to one skilled in the art.

The regulation of the compaction force of a sealing device, for example a roller seal, is particularly useful since the used compaction force significantly affects the structure of the granule, as well as the fraction of small particles and / or small granules. The compaction force depends on many parameters, such as the speed of rotation of the rolls and the feed rate of the powder substance. For example, the higher the feed rate of the powder substance at a given speed of rotation of the roller, the higher the compaction force.

Conveyor material 102 may be, for example, polyvinyl chloride (PVC), such as PVC, approved by the US Food and Drug Administration (FDA PVC). The various components of the system can be interconnected by electrical wires for grounding purposes. Preferably, the entire system is grounded.

FIG. 2 a shows a roller seal 200 with which a mass 203 is compressed containing raw materials and possibly particles recycled from a fractionating device to obtain a belt 204, 205, 206 using rolls 201, 202. by which mechanical force to the mass intended for compaction. Depending on the compaction force applied to the mass and the thickness of the tape, the amount of mass that is compacted into granules 204, 205 changes. The remaining mass 206 can store individual small granules and / or small particles in the middle of the tape. Small granules and / or small particles individually may not be able to form acceptable granules. However, the presence of such a mass can make a positive contribution to the formation of acceptable granules at process steps such as fractionation and / or transportation, for example, by friction electrification and electrostatic forces. Depending on the feed material and compaction parameters, such as tape thickness, the proportion of fine particles and / or small granules may vary.

A convenient way to control the operating parameters of the system is to set the sealing force of the roller compactor at a minimum value at which at least some granules are obtained, and to set the rotation speed (see description relating to FIG. 4) of the fractionating device at the maximum value, acceptable (for example, approximately 100 rpm) in a device manufactured by ROTAB ™ (Warren, Michigan, USA) and model 400EC / 200, and then adjusting the flow rate of the carrier gas so that acceptable granules with the required characteristics stream began to emerge from the system. Too small a gas flow rate in the fractionating device causes an increase in the fraction of small particles and / or small granules in the mass of the received granules, while using too large a gas flow rate results in a large proportion of acceptable granules being sent to unnecessary reprocessing. The optimal gas flow rate can be set manually or automatically, for example, using real-time measurements of the flow of received granules and the characteristics of these granules. One such measuring structure is shown in FIG.

FIG. 2b illustrates an example of creating undesired dense granules and / or hard bridge-containing granules 210, 211 when a high compaction force is used, as in the prior art. The more dense granules are present in the mass, the lower quality the tablet mass can have. Although the flowability characteristics of the mass obtained using high prior art compaction forces (or repetitive consolidations with lower efforts) may be acceptable even without fractionation, compressibility and / or tabletability of the mass may be significantly lower for some materials, or some other tablet characteristics, such as disintegration time, may be unsatisfactory. Moreover, significant heating of the material can be observed at the stage of compaction of the granulation method of the prior art, leading, for example, to the formation of solid bridges by crystallization and / or decomposition of the components of the granules or to unsatisfactory characteristics of the granular mass. Moreover, the application of high compaction forces usually reduces the proportion of small granules and / or small particles 206 in the resulting granular mass. Too low a percentage of such small granules and / or small particles at such stages of the process as fractionation and / or transportation can adversely affect the quality of the received granules.

Figure 2c shows an image obtained by scanning electron microscopy (SEM) of an exemplary dense corn starch granule obtained using high compaction forces (e.g., greater than 80 kN using a Hosokawa Bepex Pharmapaktor L200 / 50P roller compactor) for corn starch (CERESTAR ™, product code C * Gel 03401, batch number SB4944), typical of prior art dry granulation processes.

FIG. 2d shows an example of an exemplary porous starch granule from the same starch, which was obtained using a low compaction force (in this case, 30-35 kN using the same Hosokawa roller compactor) and then fractionated using a gas stream according to an embodiment of the present invention. For various materials, the "low compaction force" by which porous granules are obtained, and the "high compaction force" by which an unacceptable amount of dense granules and / or granules with hard bridges are obtained can vary. It was observed that the surface of the granule of FIG. 2c is less porous (i.e. more dense) than the surface of the granule of FIG. 2d. In the porous granule in FIG. 2d, there is more free space (i.e., pore) between the individual particles than in the dense granule in FIG. 2c. Also, apparently, on the surface of the porous granule in Fig.2d there is a greater part of the loose particles than on the dense granule in Fig.2c. Further, the granule in Fig. 2c has more faces than the granule in Fig. 2d. The rounded shape of the porous granule can contribute to the good flowability of the granular mass containing such granules. Pores between particles on the surface of the porous granule, as shown in Fig.2d, can improve the compressibility of the granules.

Figure 2e shows another embodiment of the granules of the present invention. Image 250 shows a plurality of granules 251 of 100% paracetamol obtained using a plant according to one embodiment of the invention. In the granulation process, a compaction force of 60 kN was used. According to the applicant’s observation, paracetamol can be granulated using higher compaction forces than most other materials. Unless otherwise indicated, the fractionation apparatus used in the process of this and the following examples is similar to that described in FIG. 4 and FIG. 5c. A typical granule size of 251 in this sample is from 500 to 1000 microns. Image 252 shows an enlarged picture of the surface of one such granule. In the image 252, it can be observed that the densified surface 254 of the granule is covered mainly with small granules 255 (for example, from about 5 μm to 50 μm). Such individual small granules 257 are also shown in image 256. Small granules 255 are relatively loosely attached to the granule 251, forming the porous surface of the granule. Thus, although the used compaction force was higher than with typical materials, the surface of the resulting granules is porous, as can be visually observed. Applicant contemplates that small granules and / or small particles can be attached to large granules by electrostatic forces generated, for example, by friction electrification during the fractionation step. The applicant further suggests that the porous surface formed by loosely attached small granules on the surface of the received granule can make a significant positive contribution to the flowability and tableting properties of the granular mass.

Figure 2f shows another embodiment of the granules of the present invention. Image 260 shows a plurality of excipient granules 261 including 70% microcrystalline cellulose and 30% corn starch. In the granulation process, a compaction force of 16 kN was used. A typical granule size 261 in this sample is from 500 to 1000 microns. Image 262 shows an enlarged surface picture of one of such granules. In image 262, it can be observed that the compacted surface of the granule is covered with small granules and / or small particles 263 (for example, in the range of about 5 μm to 100 μm). Such individual small granules 265 and individual small particles 266 are also shown in image 264. Small granules 265 and small particles 266 are relatively freely attached to the granule 261, forming the porous surface of the granules. The proportion of small granules (in this example, granules less than 106 μm) was approximately 20%. The observed flowability of the mass was excellent.

Figure 2g illustrates the formation of granules from a raw material comprising 50% microcrystalline cellulose and 50% corn starch. Image 270 shows an SEM image of the raw material. Image 271 shows an SEM image of a compacted, but not yet fractionated, granular mass. In the experiment, a compaction force of 25 kN was used. Image 272 shows an SEM image of a granular mass received by a fractionating apparatus according to one embodiment of the present invention. The magnification of the images 270 and 271 is essentially the same, and the image 272 has an increase of 0.1 compared with the images 270 and 271. In the image 270 practically no granules are visible. In the image 271, the relatively small size of the granules obtained in the compaction step is noteworthy. The granules in the compacted mass 271 formed by a roller compactor and a device for grinding flakes (110 and 111 in FIGS. 1a and 1b) are generally less than 500 μm, while most of the granules 272 received by the fractionating device (see FIG. .4), greater than 500 microns. This unexpected observation leads the applicants to suggest that new acceptable granules may form and / or granules may further agglomerate in the fractionation step of the process of one embodiment of the present invention.

FIG. 2h shows graphs of particle size distribution for the materials shown in images 271 and 272 of FIG. 2g. According to the product certification data for the raw materials used, the particle size distribution of the raw material (not shown in the figures) is such that almost all particles are less than 106 microns in mass. After the mass is compacted, the proportion of granules of an acceptable size slightly increases, as shown in image 280, but most of the particles (approximately 73%) still have sizes less than 106 microns. Image 281 shows that after separation into fractions, the proportion of granules greater than 106 μm increases significantly. The accepted fraction still contains about 10% of small granules and / or small particles less than 106 microns. Despite the relatively large proportion of small granules and / or small particles, the mass shows excellent flowability. The total fraction of granules received from the compacted mass at the fractionation stage was approximately 10%. Thus, approximately 90% of the mass was not taken up by the fractionator.

FIG. 2i shows SEM images of the surfaces of granules made using embodiments of the present invention. In the granulation process, various compaction forces were used. The material shown includes 50% microcrystalline cellulose and 50% corn starch. Pictures 290, 291, 292 show granules obtained using a compaction force of 25 kN, 40 kN, and 60 kN, respectively. Noteworthy is the decrease in surface porosity when the compaction force increases. You can easily detect many pores in the granules of images 290 and 291, while there are large dense areas in the granules of image 292. The lack of pores on the surface of the granules can worsen at least some of the properties of the granular mass, for example, flowability, tabletability and / or disintegration of the resulting tablet. Thus, it has been proposed that the optimum compaction force for producing granules from this raw material is probably less than 60 kN. Although SEM images 290, 291 do not show significant differences in the surface structure of the granules, the granular mass obtained using a compaction force of 25 kN gives tablets with higher tensile strength and faster disintegration than the mass obtained with a compaction force of 40 kN.

FIG. 3 shows, by way of example, a fractionating device for removing fine particles and / or small granules from the granular mass 303 obtained by means of a compactor. The device has a camera 300, which is made with holes for various purposes. The incoming material 301 from the seal and the device for grinding flakes is fed through one or many holes 302. Gravity causes the material 305 to roll down towards the hole 304, through which the received granular mass 306 is poured from the system into the container. Through the same hole 304, carrier gas 307 (air) enters the system. The gas can also enter the system through some other opening, which is positioned so as to achieve the desired effect of removing fine particles and / or small granules by a carrier gas stream. The carrier gas flows in a direction that is different from (opposite to) the flow of received granules. The received granules are poured from the device 300 for fractionation through the pipe 304 under the action of gravity. While the granules are transferred to a fractionator 300, small particles and / or small granules can agglomerate with other granules, thereby further increasing the granules. Small particles and / or small granules 308 are carried away from the fractionating device by a carrier gas stream 309 through aperture 310. There may be many openings for received granules, as well as for unaccepted small particles and / or small granules.

Figure 4 illustrates an example of an improved fractionation device. In the drawing, the components and structures inside the device are drawn in dashed lines. The device 400 includes a fractionating chamber and an open cylinder 401 mounted inside the chamber (or a conical device, not shown) mounted rotatably on rollers 410. The cylinder rotation speed can be adjusted so that it is, for example, as accessible as possible in the device manufactured by ROTAB ™ (Warren, MI, USA) and 400EC / 200. The shell of the cylinder or cone may be provided with holes. There are no restrictions on the number and shape of the possible openings or their edges, except that the openings must be designed so that the gas (air) together with the involved small particles can leave the cylinder through them. The openings can be, for example, round, oval or slit-like. In one embodiment, the holes are round and can be cut using laser cutting technology. In one embodiment, the diameter of the round holes is 1.5 mm. The drive motor 402 is mounted in order to rotate the cylinder at a suitable speed, for example, 100 rpm. The spiral structure 403 is formed inside the cylinder for transporting solid material from the supply end 411 to the outlet 404 as the cylinder rotates. Instead of a spiral structure, different types of ribs or other structures can be installed inside the cylinder to allow the compacted material to move and interact with the gas flow. The desired angle of the cylinder can be set, for example, by changing the location of the entire device 400 for separation into fractions in its suspension structure 413, 414.

The powder 405 exiting the sealing device is poured through the feed connection 412 to the cylinder feed end 411 and is transported by means of a spiral structure 403 towards the outlet pipe 404. The carrier gas flowing through the outlet 404 moves in the opposite direction with respect to the received granules 407. Acceptable granules extend along cylinder 401 and spill out through outlet 404 into a product container (not shown) by gravity. Unacceptable small particles and / or small granules that may accompany acceptable granules when passing into pipe 404 are typically transported back from pipe 404 to cylinder 401 by gas stream 406. In the present apparatus, outlet 404 is a downwardly oriented pipe of length 70 mm and diameter 40 mm. The unaccepted fraction 408 of fine particles and / or small granules, together with the carrier gas stream, enter the feed conveyor (see 102 in FIG. 1) through connection 409 for reprocessing. Granules may increase in size in a fractionating device 400 (or 300 in FIG. 3). This agglomeration can be caused, for example, by friction electrification and electrostatic forces.

The properties of the received fraction can be influenced, for example, by changing the cylinder rotation speed, the angle of the cylinder, the pitch of the spiral and the size, number, location and shape of the holes in the cylinder, as well as by changing the flow rate of the carrier gas.

FIGS. 5a and 5b show two different views of a cylindrical device located inside a fractionating device (see 400 in FIG. 4). The cylinder 500 has openings 501, which in FIG. 5a are located throughout the cylinder liner, while in FIG. 5b, openings are located at only one end of the cylinder. The incoming material 502, which contains both granules and fine particles, is fed into the rotating cylinder through one end of the cylinder. The rotational movement 503 of the cylinder 500 and the spiral (see 403 in FIG. 4) inside the cylinder pushes incoming material toward the other end of the cylinder. As the material moves in the cylinder, the carrier gas stream 504 separates the acceptable granules from the unacceptable fine particles and / or small granules 505 that are transported from the cylinder through the holes 501 by the carrier gas stream. Received granules 506 are ultimately expelled from the cylinder by means of a spiral structure that is located inside the cylinder.

In the embodiment shown, the rotating device is a cylinder with a diameter of 190 mm and a length of 516 mm and includes holes, each of which has a diameter of 1.5 mm, and the holes are at an average distance of 6 mm from each other. The flow of air that enters the fractionating device through the opening 404 (FIG. 4) is then removed from the fractionating chamber through the opening 409 (FIG. 4) with a diameter of 50 mm for reprocessing. Inside the cylinder is a helical guide structure that advances the received material 506 by 80 mm per revolution towards the hole. The height of the guide structure is 25 mm. Fig. 5c shows a drawing of an exemplary stainless steel perforated sheet that can be used to create a suitable cylinder. The sheet thickness is approximately 0.8 mm. The ROTAB ™ device described above was modified by replacing the cylinder with a cylinder assembled from the steel sheet of FIG. 5c, and the fractionating chamber was changed to have a shape similar to that shown at 400 in FIG. 4.

Although the devices shown in FIGS. 5a and 5b have open ends and a cylindrical shape, and the movement used is rotational movement, transporting devices of other shapes using other types of movement can also be used to transport the mass in a fractional flow of air.

The device can be adapted to improve its continuous processing capabilities. One such modification is shown in FIG. 6, which illustrates a dual filter assembly. Most of the small particles and / or small granules are separated from the carrier gas, for example, air in the cyclone 602 (see also 106 in Fig. 1a or 1b), however, some small particles and / or small granules can be sucked out of the cyclone using gas -carrier. Such particles may need to be filtered out before the carrier gas leaves the system. Filters 607a, 607b collect fine particles and / or small granules until the filter is cleaned. One of the filters 607a, 607b may be active when the other is cleaned, for example, by vibration. Valves 605, 612 can be used to direct the gas flow through the active filter and to disconnect the cleaned filter from the gas flow. The powder obtained by cleaning the filter falls below the filter and then into the pipe 609a, 609b when the valve 608a, 608b is respectively open. At the other end of the pipe, a lower valve 610a, 610b may be located, which is opened after the upper valve 608a, 608b is closed. Opening the bottom valve causes the powder to fall down onto the circulation, followed by reprocessing. This arrangement makes it possible to clean one of the filters, while the installation is working, and cleaning does not lead to undesirable jumps in the pressure of the carrier gas in the installation.

Also, the installation can be equipped, for example, with sensors that measure the size of the received granules in real time. This design is shown in Fig.7. The received granules leave the device 700 for fractionation through the pipe 701. Light-emitting devices 702, as well as photosensitive sensors 703, are installed in the pipe to monitor the size of the passing received granules. Based on the information received from the sensors, the control logic of the system can adjust the operating parameters of the installation. One of these adjustable parameters may be, for example, the size of the granules obtained by the screen 704 for grinding flakes. Another such custom parameter may be the gas flow rate of the system.

On Fig illustrates as an example a possible design for granulating powders separately and subsequent mixing of the granules with each other. Properties, for example, disintegration of the final product, for example, tablets, can be influenced by granulating the components of the composition in a variety of granulation processes, in contrast to when granulation is carried out in a single process.

In each of the granulation systems 801, 802, granules are obtained from different substances (or from the same substance, but with different granulation parameters, such as compaction force or size of received granules). Each such system has its own means 811, 812 for setting granulation parameters. Accepted granules from each granulation system are passed through a conveyor 803, 804 to a granule mixer equipped with means 806, 807 for controlling the amount of each type of granules in the final mixture, the mixer can also be equipped with means 808 for mixing granules before the granulated mass enters the container 810 for the final product or directly into a tabletting machine (not shown). The conveyor 803, 804 in Fig. 8 is a pipe that leads to the mixer, however, the conveyor can also direct the granules into an intermediate storage container from which the mass can be transported to the mixer.

Figure 9 illustrates a simple device for measuring the flowability of a powder or granular mass. Devices of various sizes are used to determine various degrees of flowability. The degree of fluidity can be satisfactory, good, very good or excellent.

A device for determining satisfactory flowability includes a cone 900 with a smooth plastic surface, height 901, component 45 mm, and with an angle of 902 tapers of approximately 59 degrees and a circular hole 903, the diameter of which is 12 mm The tube 904 is 23 mm long. In the study of the flowability of the material, the cone is filled with powder or granular mass, while the circular hole 903 is closed. The hole is opened, the cone is slightly struck to start the rash, and the powder spills through the hole under the influence of only gravity. Additional shaking or other kind of cone movement during the test is not allowed. The material passes a flow test if the cone remains substantially empty. “Essentially” here means that at least 85%, 90%, or 95% of the powder leaves the cone.

A device for determining good flowability using the method explained above includes a cone 900 with a smooth glass surface, height 901, component 50 mm, diameter 905 of the cone component 70 mm, and a round hole 903, the diameter of which is 7 mm The tube 904 is 70 mm long.

A device for determining very good flowability includes a cone 900 with a smooth plastic surface, height 901, component 35 mm, and a diameter 905 of the cone, component 48 mm, and a round hole 903, the diameter of which is 4 mm. The tube 904 is 50 mm long.

The device for determining excellent flowability includes a cone 900 with a smooth plastic surface, height 901, component 40 mm, and a diameter 905 of the cone, component 55 mm, and a round hole 903, the diameter of which is 3 mm The tube 904 is 60 mm long.

Using the above or other embodiments of the present invention, it is possible to obtain granules that have one or many of some of the required common characteristics, for example, good flowability, good compressibility, good tableting, fast disintegration of the tablet and high drug content. As observed, such characteristics are applicable to many APIs and excipients. Thus, for many APIs, it is possible to avoid some of the possible, time-consuming and costly steps of the prior art formulation process. The embodiments shown are also relatively cost effective in construction and use. For example, it is possible to create a structure that is capable of producing several kilograms or tens of kilograms of granules per hour. The method is also relatively simple and easily adjustable in comparison, for example, with prior art wet granulation methods. In the shown embodiments, there are several parameters that may need to be adjusted.

The percentages given here (%) are% by weight, unless otherwise indicated.

Averages are geometric averages unless otherwise indicated.

The following examples describe the characteristics of some typical granules and tablets that can be achieved using embodiments of the present invention.

EXAMPLES

To determine the characteristics of the granular mass according to various embodiments of the invention and its tableting, a number of tests were carried out. In all tests, the method and installation described in this document (for example, Fig. 1b and Fig. 4) were used. The gas flow rate in the installation was controlled so that the effect of separation into fractions by the gas flow led to the granular mass having good, very good or excellent flowability. The gas flow rate in the tests was provided during operation of an exhaust fan (BUSCH ™ Mink MM 1202 AV) of the system at a default speed of approximately 1860 rpm. For some materials, the speed was changed from the default to achieve the desired quality of the granular mass. The compaction force of the roller compactor was adjusted to obtain granules with optimal tabletting characteristics. The force used was recorded in kilonewtons as indicated by the roller seal (HOSOKAWA Berech Pharmapaktor L200 / 50P) used in the tests. The diameter of the rolls of the seal is 200 mm and the width of the working surface is 50 mm. The thickness of the tape obtained by the seal is approximately 4 mm. The speed of rotation of the rolls is usually from 10 to 12 rpm The exact speed of rotation is controlled by a roller seal to achieve the required sealing force. The default size of the screen for grinding flakes is 1.00 mm. In some embodiments, the size of the cereal grinding screen was changed from the default value.

Unless otherwise indicated, the rotary device shown in FIG. 4, operated at about 100 rpm, was used as a fractionation means in a test apparatus. By default, the cylinder bore size of the rotating means was 1.5 mm.

In all tablet tests, 0.25% magnesium stearate was added to the granular mass before tabletting.

The estimated particle size of the corn starch for testing ranged from 5 to 30 micrometers.

The tensile strength of the tablets was measured using a measuring device manufactured by MECMESIN ™ (Mecmesin Limited, West Sussex, UK), model BFG200N.

The particle size distribution for the granular mass was measured using a set of sieves. In these measurements, a set of four sieves was shaken for 5 minutes using an Electromagnetic Sieve Shaker (manufactured by CISA Cedaceria Industrial, S. L, model RP 08) with a power setting of 6. The hole sizes of the sieves used were 850 μm, 500 μm, 250 μm and 106 μm.

Example 1 tabletting - 90% acebutolol · HCl

5.00 kg of a powder mass containing 90% of powder of acebutolol · HCl (average particle size of 27 μm) and 10% of starch were mixed. A compaction force of 40 kN was used to compact the mass to produce granules having an average size of 877 μm and a standard deviation of 1.421 after fractionation. The bulk density without the brittleness of the resulting mass was 0.68 g / ml and the mass had good flowability. Round tablets 10 mm in diameter and weighing 500 mg were obtained using a tabletting force of 6-8 kN. The average tensile strength of the tablet was 80 N (N = 10). The observed disintegration of the tablet was approximately 6.5 minutes in water at a temperature approximately equal to body temperature.

Example 2 tabletting - 20% fluoxetine · HCl.

A powder mass containing 20% (2.24 kg) of fluoxetine · HCl (manufactured by SIFAVITOR Spa, Casaletto Lodigiano, Italy, lot number 2700/01/06), 64% (7.168 kg) of microcrystalline cellulose (EMCOCEL CAS No. 9004- 34-6, batch 5S3682) and 16% (1.792 kg) of corn starch (CERESTAR Mat. No. 03401, batch 01015757). A compaction force of 35 kN was used to compact the mass to produce granules having an average size of 461 μm and a standard deviation of 2.358 after fractionation. The size of the screen for grinding flakes was set to 1.25 mm. The bulk density without bother of the resulting mass was 0.595 g / ml and the mass had good flowability. Round tablets of 6 mm in diameter and with an average weight of 112 mg (N = 10, standard deviation = 1.89%) were obtained using the maximum tabletting force, which did not produce any destruction of the pressed workpiece along the diagonal planes. The average tensile strength of the tablet was 44 N (N = 10, standard deviation = 11.17%). The observed disintegration of the tablet was approximately 10 seconds in water at a temperature approximately corresponding to body temperature.

Example 3 tabletting - 60% paracetamol

About 4.0 kg of a powder mass containing 60% fine paracetamol powder was mixed (manufactured by Mallincroft Inc., Raleigh, USA, batch 7845906C563, 59% particles less than 20 microns, 96% particles less than 75 microns), 20% microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, batch 5S3689) and 20% corn starch (CERESTAR Mat. No. 03401, batch 01015757). A compaction force of 30 kN was used to compact the mass to produce granules having an average size of 645 μm and a standard deviation of 1.464 after fractionation. The size of the screen for grinding flakes was set to 1.00 mm The bulk density without bother of the resulting mass was 0.586 g / ml and the mass had good flowability. Round convex tablets 10 mm in diameter and with an average weight of 454 mg (N = 10, standard deviation = 0.6%) were obtained using the maximum tabletting force, which did not produce any destruction of the pressed workpiece along the diagonal planes. This was a very good result, since before it was considered difficult, if not impossible, to obtain a tablet with a high paracetamol content by pressing granules obtained using dry granulation methods. The average tensile strength of the tablet was 49 N (N = 10, standard deviation = 12.73%). The observed disintegration of the tablet was less than 1 min in water at a temperature approximately corresponding to body temperature.

Tableting Example 4 - 90% Sodium Valproate

5.56 kg of a powder mass containing 90% sodium valproate (manufactured by Chemische Fabrik Berg), 5% hypromellose (PHARMACOAT 606, lot 5115055) and 5% corn starch (CERESTAR Mat. No. 03401, lot 01015757) were mixed. A compaction force of 35 kN was used to compact the mass to produce granules having an average size of 550 μm and a standard deviation of 1.666. The size of the screen for grinding flakes was set to 1.25 mm. The bulk density without bother of the resulting mass was 0.532 g / ml and the mass had good flowability. Round convex tablets 12 mm in diameter and with an average weight of 560 mg (N = 10, standard deviation = 1.29%) were obtained using the maximum tabletting force, which did not produce any destruction of the pressed workpiece along the diagonal planes. The average tensile strength of the tablet was 84 N (N = 10, standard deviation = 11.80%). Due to the fact that hydromellose introduced as an excipient imparts characteristics of slow release, the observed disintegration of the tablet was approximately 40 minutes in water at a temperature approximately corresponding to body temperature.

Example 5 tabletting - 50% ketoprofen

About 8.0 kg of a powder mass containing 50% ketoprofen (manufacturer Ketoprofen S.I. M. S. Societa italiana medicinali Scandicci, batch 121.087, 79% of particles less than 60 μm) and 50% corn starch (CERESTAR Mat. No. 03401, batch SB4944) were mixed. A compaction force of 40 kN was used to compact the mass to produce granules having an average size of 900 μm and a standard deviation of 1.418. The size of the screen for grinding flakes was set to 1.00 mm The bulk density without brittle mass was 0.625 g / ml and the mass had good flowability. Round convex tablets 6 mm in diameter and with an average weight of 94 mg (N = 10, standard deviation = 1.94%) were obtained using the maximum tabletting force, which did not produce any destruction of the pressed workpiece along the diagonal planes. The average tensile strength of the tablet was 39 N (N = 10, standard deviation = 14.56%). The observed disintegration of the tablet was approximately 10 seconds in water at a temperature approximately corresponding to body temperature.

Example 6 tabletting - 80% metformin · HCl

Approximately 4.0 kg of powder mass containing 100% metformin · HCl (supplier SIMS trading (Florence, Italy), lot 21.039) was compacted using a compaction force of 35 kN to obtain granules having an average size of 668 μm and a standard deviation of 1.554. The size of the screen for grinding flakes was set to 1.00 mm The bulk density without brittle mass was 0.694 g / ml and the mass had good flowability. Separately, excipient granules containing 70% microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, batch 5S3689) and 30% corn starch (CERESTAR Mat. No. 03401, batch 01015757) were mixed and granulated using the same compaction force. Then 80% of metformin granules were mixed with 20% excipient granules and compressed into tablets. Round convex tablets of 12 mm in diameter and containing 500 mg of metformin were prepared using the maximum tabletting force, which did not produce any destruction of the pressed preform along the diagonal planes. The average tensile strength of the tablet was 59 N (N = 3). Disintegration of the tablets was not determined.

In addition to the tabletting examples, the compressibility and flowability of the granular mass was checked according to embodiments of the invention, by measuring the Hausner index of the mass and determining the mass flowability. Methods suitable for calculating the Hausner exponent and determining the flowability of the mass are described earlier in this document.

Example 1 flowability -100% paracetamol

4.0 kg of a powder mass containing 100% paracetamol (manufactured by Mallincroft lnc.-Raleigh, USA, batch 6088906C107) was compacted using a compaction force of 12 kN and a screen for grinding flakes with a mesh size of 1 mm to obtain granules having an average size of 708 μm and a standard deviation of 1.349 after fractionation. 0.58% of the mass granules had a diameter of less than 106 microns. The bulk density of the resulting mass was 0.610 g / ml and the bulk density with ustrus was 0.758 g / ml. The calculated Hausner index for the mass was 1.24. Despite the relatively high compressibility, as indicated by the Hausner index, the observed flowability of the mass was excellent.

Flowability Example 2 - 90% Metformin · HCl

A powder mass containing 90% (4.0 kg) of metformin (METFORMIN HYDROCHLORIDE USP. Batch number 17003742, USV LIMITED, BSD Marg. Govandi, Mumbai 400 088, India), 8% (356 g) microcrystalline cellulose (EMCOCEL CAS No. . 9004-34-6, batch 5S3682) and 2% (88 g) of corn starch (CERESTAR Mat. No. 03401, batch 01015757). Used a compaction force of 30 kN, a cell size of the screen for grinding flakes 1.00 mm and an exhaust fan speed of 2100 rpm to obtain granules having an average size of 477 μm and a standard deviation of 2.030 after separation into fractions. 11.0% of the mass granules had a diameter of less than 106 microns. The bulk density without utrusa of the resulting mass was 0.581 g / ml and the bulk density with utrusa was 0.714 g / ml. The measured Hausner index for the mass was 1.23. Despite the relatively high compressibility, as indicated by the Hausner index, the observed flowability of the mass was excellent. When conducting experiments with metformin, an unexpected observation was also made that although 100% fine metformin powder showed strong agglomeration (forming large, solid agglomerates) when stored at room temperature and ambient humidity, 100% metamorphine granules made from such a powder using the method inventions showed almost no such agglomeration during storage.

Flowability Example 3 - Excipient

About 3.0 kg of a powder mass containing 70% microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, lot 5S3689) and 30% of corn starch (CERESTAR Mat. No. 03401, lot 01015757) were mixed. Used a compaction force of 16 kN, a cell size of the screen for grinding flakes of 1.00 mm to obtain granules having an average size of 318 μm and a standard deviation of 2.159 after separation into fractions. 19.6% of the mass granules had a diameter of less than 106 microns. The bulk density without utrusa of the resulting mass was 0.379 g / ml and the bulk density with utrusa was 0.510 g / ml. The measured Hausner index for a given mass was 1.35. Despite the relatively high compressibility, as indicated by the Hausner index, the observed flowability of the mass was excellent.

Example 4 flowability - 20% ketoprofen

About 4.0 kg of a powder mass containing 20% ketoprofen (S.I.M.S. Society italiana medicinali Scandicci, lot 121.087) and 80% microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, lot 5S3689) were mixed. Used a compaction force of 24 kN and a screen cell size for grinding flakes of 0.71 mm to obtain granules. When the system’s exhaust fan speed was set to 1980 rpm, the average grain size received was 304 μm and the standard deviation was 2.275 after fractionation. 23.0% of the mass had a particle size of less than 106 microns. The bulk density without utrusa of the resulting mass was 0.510 g / ml and the bulk density with utrusa was 0.676 g / ml. The measured Hausner index for a given mass was 1.325. The observed flowability of the mass was satisfactory. When the system exhaust fan speed was set at 2400 rpm, the average size of the received granules was 357 μm and the standard deviation was 2.121 after fractionation. 13.7% of the mass had a particle size of less than 106 microns. The bulk density without the iron of the resulting mass was 0.521 g / ml and the bulk density with ustrus was 0.714 g / ml. The measured Hausner index for this mass was 1.371. The observed flowability of the mass was excellent. This example shows that by changing the gas flow in the system, you can get a granular mass with different flow characteristics. This example also shows that, unlike what is described in the prior art, for example, US Pat. No. 6,752,939, the Hausner exponent does not necessarily predict granular mass flowability. For example, the size distribution of granules for a granular mass can have a greater effect on flowability than the compressibility of a granular mass. Good compressibility and flowability can thus be jointly present in the same granular mass.

Performance example

The embodiments disclosed in this description are capable of producing a significant amount of granular mass. In a performance test of one embodiment, including the fractionating device of FIG. 4, 5.98 kg of paracetamol (7845 Paracetamol Fine Powder, Mallincroft Inc. - Raleigh, USA, batch 7845906C563), 10.69 kg of microcrystalline cellulose (CAS) were mixed no. 9004-34-6 - JRS PHARMA LP - Patterson (USA), batch 5S3689), 37.10 corn starch (CERESTAR Mat. n.03401, batch 01015757), 12.19 kg of lactose (LACTOSE MONOHYDRATE - DMV International Pharmatose 80M DP5500, batch 10209285 906535704), 34.04 kg pulp (Technocel - CFF - GmbH - Gehren Germany, batch G 13060620) and granulated using a compaction force of approximately 40 kN and an exhaust fan speed RA 2160 rev / min. The installation was operated for two hours and 38 minutes, obtaining 94.66 kg of granules, which had at least good flowability characteristics.

Fractionation Example 1

About 5.0 kg of a powder mass containing 50% microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, batch 5S3689) and 50% corn starch (CERESTAR Mat. No. 03401, batch 01015757) were mixed and granulated. In the granulation process, re-processing of the unaccepted fraction was prevented. To achieve this, the mass to be processed was fed manually into an intermediate vessel (107 in Fig. 1b), from which it was transported to the seal (110 in Fig. 1b) by opening the valve (109 in Fig. 1b) before starting the process. Then the process began and 5.0 kg of the mass was granulated and divided into fractions. During processing, the valve (109 in FIG. 1b) was kept closed to prevent re-processing of the unaccepted fraction. A compaction force of 40 kN and a screen cell size for grinding flakes of 1.00 mm were used to obtain granules having an average size of 523 μm (standard deviation of 1.70) after fractionation. During the test received 1630 g (32.6%) of the taken granules. An SEM image of the surface of the received granule is shown in image 291 of Fig. 2i. The rest of the mass was rejected by the device for separation into fractions. 4.0% of the granules / particles of the accepted mass had a diameter of less than 106 microns. The bulk density without utrusa of the resulting mass was 0.56 g / ml and the bulk density with utrusa was 0.641 g / ml. The measured Hausner index for a given mass was 1.15. The observed flowability of the accepted fraction was excellent. On the other hand, the observed fluidity of the unaccepted fraction was unsatisfactory.

The unaccepted fraction contained 16.4% of granules of more than 250 microns, while the accepted fraction contained 92% of granules of more than 250 microns.

In order to determine the tabletability of the accepted fraction of the granular mass, 0.5% magnesium stearate was added to the mass and tablets with an average weight of 588 mg were obtained. The measured average tensile strength of the tablet (N = 6) was 23.56 N and the standard deviation was 1.308. The observed disintegration of the tablet was approximately 12 seconds.

Fractionation Example 2

About 4.0 kg of a powder mass containing 50% microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6, lot 5S3689) and 50% corn starch (CERESTAR Mat. No. 03401, lot 01015757) were mixed and granulated. In contrast to the above examples, in the fractionation step of the method, a fractionation apparatus according to the embodiments of Figs. 1a and 3 of this description was used. In the granulation process, re-processing of the unaccepted fraction was prevented. To achieve this, the mass to be processed was manually fed into the intermediate vessel (107 in Fig. 1a), from which it was transported to the seal (110 in Fig. 1a) by opening the valve (109 in Fig. 1a) before starting the process. Then the process was started and 4 kg of the mass was granulated and divided into fractions. During processing, the valve (109 in FIG. 1 a) was kept closed to prevent re-processing of the unaccepted fraction. A compaction force of 16 kN and a screen cell size for grinding flakes of 1.00 mm were used to obtain granules having an average size of 473 μm (standard deviation 2.42) after fractionation. During the test, 670 g (16.75%) of the taken granules were obtained. The rest of the mass was rejected by the device for separation into fractions. 20.9% of the granules / particles of the accepted mass had a diameter of less than 106 microns. The bulk density without utrusa of the resulting mass was 0.455 g / ml and the bulk density with utrusa was 0.568 g / ml. The measured Hausner index for a given mass was 1.248. Despite the high compressibility of the received mass, as indicated by the Hausner indicator, the flowability observed was excellent. On the other hand, the observed flowability of the unaccepted fraction was unsatisfactory.

The unaccepted fraction contained 7.1% of granules of more than 250 microns, while the accepted fraction contained 68.4% of granules of more than 250 microns.

In order to determine the tabletability of the accepted fraction of the granular mass, 0.5% magnesium stearate was added to the mass and tablets with an average weight of 584 mg were obtained. The measured average tensile strength of the tablet was 63.34 N and the standard deviation was 6.78 (N = 6). It should be noted that the tensile strength of the tablet is significantly higher than in Example 1 fractionation. The observed disintegration of the tablets was 12 seconds.

For those skilled in the art, the above-mentioned exemplary embodiments illustrate the model presented in this application, on the basis of which it is possible to develop various methods, systems, granules and tablets in which the inventive concept disclosed in this application is obviously used.

Claims (36)

1. A method of producing granules from a powder, characterized in that a low compaction force is applied to the powder to obtain a compacted mass including a mixture of small particles and granules, and small particles are separated from the granules by involving small particles in a gas stream in which the compacted gas flows mass, where the direction of flow of the gas stream has a component that is opposite with respect to the direction of flow of the compacted mass. 2. The method according to claim 1, in which the compaction force is low enough that 75 wt.% Or less of the powder is compacted to obtain acceptable granules having a particle size of more than 150 μm, and the remaining amount of the powder remains in the form of fine particles and / or small granules. 3. The method according to claim 1, in which the compaction force is applied to the powder through a process involving the use of a roller compactor to obtain a tape of compacted powder, which is crushed to obtain granules. 4. The method according to claim 1, wherein the compaction force is a compaction force of 60 kN or less for the Bepex Pharmapactor L200 / 5 0P Hosakawa ™ roller seal. 5. The method according to claim 1, wherein the compaction force is a compaction force of 16 kN or more for a Bepex Pharmapactor L200 / 50P Hosakawa ™ roller seal. 6. The method according to claim 1, characterized in that said compacted mass is moved in said gas stream using mechanical means. 7. The method according to claim 1, in which the fine particles are separated from the granules by means of an apparatus including fractionation means, in which the fractionation means includes a rotating device, such as a cylinder or cone, along the axis of which the compacted mass is moved in said gas stream . 8. The method according to claim 7, in which the movement of the compacted mass along the axis of the rotating device is directed by means of a spiral structure. 9. The method according to claim 1, in which the fine particles are separated from the granules by means of an apparatus comprising fractionation means made with openings in which small particles and / or small granules are drawn. 10. The method according to claim 9, in which the holes have a minimum size of 1.0x to obtain granules with the desired average size x. 11. The method according to claim 1, in which the fine particles are separated from the granules by means of an apparatus comprising fractionation means, in which the residence time of the compacted mass inside the fractionation means is at least 2 s. 12. The method according to claim 1, characterized in that said powder comprises an excipient used in pharmaceutical products and / or an active pharmaceutical ingredient. 13. The method according to item 12, in which the specified powder contains the active pharmaceutical ingredient in an amount of at least 60%. 14. The method according to claim 1, in which the entrained fine particles and / or small granules are fed by recycle for compaction. 15. The method according to any one of claims 1 to 14, further comprising the step of collecting granules. 16. The granular mass obtained by dry granulation, containing granules obtained by the method according to item 15. 17. The granular mass obtained by dry granulation, characterized in that it contains granules with an average size of from 100 μm to 3 mm, consisting of (a) a dense core containing fine particles of material bound by van der Waals forces, and (b) a coating layer containing fine particles and / or small granules of the specified material associated with the specified dense core by electrostatic forces. 18. A granular mass obtained by dry granulation, characterized in that it contains granules having an average size of from 100 μm to 3 mm, consisting of (a) a dense core containing fine particles of material bonded by van der Waals forces, and ( b) a porous coating layer containing fine particles and / or small granules of the specified material. 19. The granular mass obtained by dry granulation according to 17 or 18, characterized in that the average particle size of the material to be compacted is 1-100 μm, and the average size of the dense core of the granule is 100-3000 μm, and the ratio of the average size of small particles and / or small granules of the material of the coating layer of the granules to the average size of the dense core of the granules is at least 1:10. 20. The granular mass obtained by dry granulation, according to any one of paragraphs.16-18, characterized in that it can be tabletted and it has good flowability and includes at least 10% of at least one of the following pharmaceutical ingredients:
- acebutolol · HCl,
- fluoxetine · HCl,
- paracetamol,
- sodium valproate,
- ketoprofen and
- metformin · HCl. 21. The method according to claim 12 or the granular mass obtained by dry granulation according to claim 17 or 18, wherein the material powder comprises an active pharmaceutical ingredient selected from acebutolol · HCl, fluoxetine · HCl, paracetamol, sodium valproate, ketoprofen and metformin · HCl. 22. A method of preparing a tablet, comprising pressing a granular mass obtained by dry granulation, according to any one of paragraphs.16-19, possibly mixed with one or more additional excipients. 23. The tablet obtained by the method according to item 22. 24. The tablet according to item 23, comprising at least 10% of at least one of the following active pharmaceutical ingredients:
- acebutolol · HCl,
- fluoxetine · HCl,
- paracetamol,
- sodium valproate,
- ketoprofen and
- metformin · HCl. 25. Installation for dry granulation, characterized in that it includes a means of compaction, capable of creating a low compaction force, and means of separation into fractions, adapted to separate small particles from the compacted mass by involving small particles in the gas stream in which the compacted mass flows, where the direction of flow of the gas stream has a component that is opposite with respect to the direction of flow of the compacted mass. 26. The installation according A.25, in which the compaction force is applied using means, including the use of a roller seal to obtain a tape of compacted powder, which is crushed to obtain granules. 27. The installation according A.25, in which the specified compacted mass is moved into the specified gas stream using mechanical means. 28. The apparatus of claim 25, wherein said fractionating means includes at least one structure for guiding said compacted mass inside said fractionating means. 29. The apparatus of claim 25, wherein the fractionating means includes a rotating device, such as a cylinder or cone, along the axis of which the compacted mass moves in said gas stream. 30. The apparatus of claim 25, wherein the fractionation means is provided with holes in which fine particles and / or small granules are drawn. 31. The installation according to item 30, where the holes have a minimum size of 1.0x to obtain granules with the desired average size x. 32. Installation according A.25, in which the means of separation into fractions does not require transmission of the compacted mass through a sieve. 33. A device for separation into fractions, adapted to separate small particles from the compacted mass by involving small particles and / or small granules in the gas stream, including a rotating device, such as a cylinder or cone, along the axis of which the compacted mass flows in the specified gas stream, moreover, the rotating device is made with holes in which small particles and / or small granules are involved, and where the direction of flow of the gas stream has a component that is opposite to the direction compacted mass flow. 34. Installation according to any one of paragraphs.25-32 or device according to clause 33, in which the direction of flow of the gas stream is essentially opposite to the direction of flow of the compacted mass. 35. The installation according to clause 29 or the device according to clause 33, in which the movement of the compacted mass along the axis of the rotating device is directed by means of a spiral structure. 36. A tablet formed by compressing a granular mass obtained by dry granulation according to any one of claims 16-19, comprising 60% or more of the active pharmaceutical ingredient selected from paracetamol, metformin · HCl, acebutolol · HCl and sodium valproate.

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