CN101557871B

CN101557871B - Granules, tablets and granulation

Info

Publication number: CN101557871B
Application number: CN2007800418114A
Authority: CN
Inventors: G·波利蒂; E·海拉卡
Original assignee: Atacama Labs Oy
Current assignee: Atacama Labs Oy
Priority date: 2006-11-10
Filing date: 2007-11-05
Publication date: 2013-02-13
Anticipated expiration: 2027-11-05
Also published as: ZA200902712B; FI20060990A0; CN101557871A

Abstract

The invention provides, inter alia, a method for producing granules from a powder, characterized in that a low compaction force is applied to the powder to produce a compacted mass comprising a mixture of fine particles and granules and separating fine particles from the granules by entraining the fine particles in a gas stream. Also provided are apparatus for use in the process and tablets formedby compression of the resultant granules.

Description

Particle, tablet and granulation

Technical field

The present invention relates to particle, tablet and their production method and equipment.

Background technology

For most of pharmaceutical preparations, tablet is one of delivery form of the most frequent use.This situation can be explained by following practical work: Tabules can guarantee the accurate dosage of the active component of pharmaceutical preparation.In addition, process and packing is easier, and the shelf life of these preparations and stability usually than other preparation better.

Above-mentioned identical demonstration also be interpreted as what often with tablet as the reason of other medium of using, described other used the product that food for example comprises cake product, flavouring agent or sweetener, detergent, dyestuff or control plant disease.

Can use two kinds of main methods (wet granulation or dry granulation) to make the particulate matter (granulate mass) of a large amount of solids, this particulate matter is that the preparation tablet is necessary.Tablet can also prepare with direct tablet compressing.Direct tablet compressing relates to tabletting method self, rather than the preparation of initial substance.

In wet granulation, usually component is mixed, and use wet adhesive to granulate.Then wet granular is sieved, then dry and randomly grinding is pressed into tablet.Wet granulation is widely used in pharmaceuticals industry, although having confirmed it is a kind of method of difficulty, main because in particle, need liquid, and tablet manufacture often has harmful effect to active pharmaceutical ingredient (APIs) and/or finished product (for example tablet).

Usually dry granulation is described as the method for the powder of controlled broken pre-pressing, the powder of described pre-pressing is by compressing (slugging) material or making material from passing through and compacting between two counter-rotational cylinders between two counter-rotational cylinders.More particularly, usually the powdery components that comprises atomic thin particle (particles) can be mixed, then its compression (compacted) is produced hard pre-compressing tablet (slugs), then, with the precompressed slice lapping with sieve, then add other composition and last compacting to form tablet.Because in the dry granulation process, substantially do not use liquid, so avoided the problem relevant with wet granulation.Although dry granulation is seemingly produced the best method of product (tablet that for example comprises APIs) in many cases, but because the challenge aspect the processing granular material in the particle of producing desired type and production process, dry granulation relatively seldom is used always.Known dry granulation method and the known problem relevant with dry granulation method have fully been described, the review paper that the PeterKleinebudde that for example delivers writes " cylinder compression/dry granulation: (Rollcompaction/dry granulation:pharmaceutical applications) used in pharmacy " in European journal of Practical Pharmacy and biopharmacy magazine (European Journal ofPharmaceutics and Biopharmaceutics) 58 (2004) 317-326 pages or leaves in scientific paper.

It has been generally acknowledged that direct tablet compressing is the method for simple and the most most economical production tablet.Yet direct tablet compressing is only applicable to the material that need not granulate before the compressing tablet.Direct tablet compressing only needs two key steps, namely mixes all compositions, and suppresses this mixture.Yet direct tablet compressing is only applicable to the material of relative minority because the composition of tablet often need to be with the processing of some granulation techniques so that it is compressible and/or improve its uniformity and flowability.

The component of tablet is described with excipient or active component usually.Active component normally triggers those compositions of pharmacy, chemistry or nutrition effect, and its only essential amount is present in the tablet so that expectation function to be provided.Excipient is inert fraction, it is comprised in order to help the preparation of formulation or change the release characteristics of active component or be used for other purpose of auxiliary activity composition.

According to its effect in preparation, excipient can be divided into for example lubricant, glidant, filler (or diluent), disintegrant, adhesive, flavouring, sweetener or dyestuff.

Lubricant be intended to improve compressed tablets from the mould of pelletizer discharge and prevent sticking in the stamping machine.

Dose glidant to improve flow of powder.Usually use glidant to help all even moulds of as one man filling of component mixture before the compacting.

Filler is the inert fraction for reducing the concentration of active component in the final preparation, sometimes as extender.In multiple situation, adhesive also plays filler.

Disintegrant be can dose to preparation, so that when tablet is placed liquid environment, disintegration of tablet and release of active ingredients helped.Disintegrating property depends on that usually there is the swelliong power in the situation in disintegrant at liquid (for example water or gastric juice).The continuity of above-mentioned expansion damage tablet configuration, thus different component is entered in solution or the suspension.

Utilize adhesive that the structure of tablet is kept together.After using enough press powers, adhesive has the ability that other component is bonded together, and it helps the integrality of tablet.

Seeking for the suitable vehicle of specific APIs and the suitable preparation method of definite excipient and APIs combination may be a kind of time-consuming work, and this work may make the design process significant prolongation of pharmaceutical preparation (for example tablet), even prolongs the several years.

Dry granulation of the prior art and wet granulation method produce solid bridge (solid bridges) between all may the particle in particle, this may be do not expect for example because they cause thing followed tablet properties unsatisfactory.The solid bridge may be caused by the crystallization of partial melting, curing adhesive or insoluble material.Partial melting can for example occur in when using high thrust in dry granulation method.When the earth pressure release in the pressing process, the crystallization of particle may occur, and particle is combined.When comprising adhesive in the solvent of granulating, it is common introducing curing adhesive in the wet granulation of pharmacy.Solvent forms liquid bridge, and will harden or crystallization once dry adhesive, thereby forms the solid bridge between the particle.The example of the adhesive that can work by this way is polyvinylpyrrolidone, cellulose derivative (for example carboxymethyl cellulose) and pregelatinized starch.The material that can dissolve in wet-granulation process (for example lactose) drying can subsequent crystallisation, as curing adhesive.

In causing the initial formation of powder-stuck and agglomerated thing (during for example stirring), electrostatic force also may be important.In general, the final strength of the not obvious enhancing particle of electrostatic force.Yet Van der Waals force approximately can be than large four orders of magnitude of electrostatic force, and can obviously strengthen the intensity (intensity of the particle of for example producing by dry granulation) of particle.The size of above-mentioned power reduces and increases with distance between the particle surface.

Except seeking the practicable preparation method of pharmaceutical preparation, preparation method's checking is necessary.When checking referred to use the method at every turn, it must produce consistently acceptable and predictable result reliably.It is quite challenging dealing with regard to above-mentioned aspect wet granulation method.Wet granulation method often is easy to the impact of the little variation of restricted standby condition.For example, in preparation process, the variation of the moisture of dry rear starch may produce the tablet of too easily moisture absorption or have the tablet of the shelf life of minimizing.When just at laboratory condition research and development pharmaceutical preparation, controlled condition relatively easily.Yet used condition is normally less in mass production environment can accurately control, therefore so that preparation method's checking becomes difficulty and time-consuming work.For direct compression process, may also be that so wherein, the quality of final products depends on the physical property of API and excipient.The little variation of above-mentioned character can cause for example segregation (segregation) and flowability problem.

Because the preparation relevant with the direct tablet compressing method with wet granulation and the validation problem of method when possibility, particularly in pharmaceuticals industry, use dry granulation technology for required.Yet dry granulation method commonly known in the art is created in particle seldom available in the method for preparing tablet thereof.Conflicting method design parameter causes obtaining compromise often, and the properties of the grain products that namely obtains may be good, but the character of other expectations is not enough or lacks.For example, the flowability of particle may be not enough, the nonhomogeneity of particle can cause that (capping) split on the top of segregation in the preparation process or tablet or some particles may have excessive hardness, all above-mentioned these may make the compressing tablet process very difficult, slow, and are impossible sometimes.In addition, the particle of batch may be difficult to be pressed into tablet.The disintegrating property of the tablet that perhaps, obtains may be suboptimal.The problems referred to above are usually relevant with nonhomogeneity and the grain structure of the particulate matter of compacting machine production.For example, for effective compressing tablet, described material may have the minuteness particle of too high percentage composition or some particles of compacting machine production may be too fine and close.

Be well known in the art, in order to obtain the tablet of homogeneous, the batch of material (bulk) for the treatment of compressing tablet should be uniformly, and should have good flowing property.

In the prior art, dry granulation method for example cylinder compresses method, and the batch of material that obtains is not homogeneous flow usually, for example owing to have relatively large (1-3mm) and the particle of densification and very little (for example 1-30 micron) particle.This may cause segregation because when (for example during the compressing tablet) delivery of particulate material matter in preparation process, prior art large, fine and close and/or hard particle and minuteness particle are mobile in a different manner usually.Because segregation, guarantee to produce normally difficulty of acceptable tablet.For above-mentioned reasons, some known devices are arranged in the art, wherein for example will little particle under the help of (cover) vibratory sieve and sometimes also have the particle of maximum from all the other particles, to separate at classification (fractionating) device.This process normally complicated with noisy, and what obtain is the batch of material that relative homogeneous flows, wherein particle is hard and is difficult to be pressed into tablet.In addition, if described material is viscosity, and screen size is enough not large, separates little particle and just become very difficult from particle.Usually in said process, the aperture of sieve must have the minimum dimension of at least 500 μ m.

Another problem that exists in the dry granulation method of prior art is to be difficult to prepare the test batch (pilot bulk) that batch of material is produced in representative in development.Like this, thrust and other compression parameter used in laboratory scale may significantly be different from the parameter that production scale is used.Therefore, the character of production batch of material (for example mobile) may significantly be different from the batch of material with the testing equipment preparation.Air screening at the spendable a kind of method for sieving of laboratory scale.A kind of air sieve method of routine comprises makes powder pass through to determine the sieve aperture of size in order to get rid of particle less than given size (particle of needs is retained in above the screen cloth, and below the particle of eliminating is sent to).Make air by sieve aperture to carry away minuteness particle.The problem that the air sieve of prior art has is that its off-capacity is to be used for the industrial production of particulate matter.In addition, when separating minuteness particle from particulate matter, depend on screen size at the sieve of air described in the separation of the material that is eliminated, it is often got rid of desirable granule from acceptable particulate matter.In addition, when the particle with undersize aspirates from sieve aperture when walking, friable particle may break in screening process.

Patent application WO 99/11261 discloses the particle that can only comprise the dry granulation of API.In the disclosed method of this application, air known in the prior art sieve is used for separating minuteness particle (less than 150 or 125 microns particles and particle) from the particle that comprises up to 100% API.It approximately is the sieve of the full-size (for example 150 microns) of the particle that is eliminated that screen size is used in screening.The particle that seems the disclosure is to use relatively high thrust to make, because the ratio of fine particle (less than 125 microns) is about 26% (seeing Table 1) at the most after compressing.The method after sieving, causes obtaining mobile homogeneous particle material, expects that this particulate matter comprises hard particle usually, and there is no particle and particle less than 150 or 125 microns.

U.S. patent US 4,161, and 516 have disclosed the composition for the treatment of airway disorders with film agent or the particle of inhalation.The method of this patent is suitable for producing the very soft particle that can burst apart in air-flow.

U.S. patent 6,752, and 939 have disclosed with the small sample capacity and come predicting of substance for the method and apparatus of the applicability of the dry granulation that compresses method through cylinder.

U.K. patent 1,558,153 disclose the method for producing the organic dyestuff material from micronized particle, the method comprises the bonding agglomerate of suppressing described micronized particle product in next life matter, pulverize the bonding agglomerate of described material, and be the particulate matter of 100-1000 micron from the material recovery size of described pulverizing.The finest particle is shifted out by air stream.

We have found now and have made improving one's methods of particle and tablet.The method is applicable to a variety of pressed powder materials, for example APIs and excipient and non-pharmaceutical product for example the chemistry and food industry in use those.

Detailed Description Of The Invention

According to the present invention, we provide the method by the powder production particle, wherein will hang down thrust and be applied to powder to produce the material (compacted mass) that compresses, the material of this compression comprises the mixture of minuteness particle and particle, and by carry away minuteness particle in air-flow minuteness particle is separated from particle.

The method also comprises the step of collecting granules usually.

As following the explanation, the method can be moved with continuous process usually.

Described process is adapted at carrying out in the situation of basic no liquid.

Powder to be used in pelletization of the present invention (for example APIs and/or can be used for the excipient of pharmaceuticals industry) comprises minuteness particle usually.In addition, described powder can have the particle mean size less than 100,50 or 20 microns usually.Minuteness particle in the powder can have the minimum particle size and 150 of 2,5 or 10 μ m, the maximum particle size of 100 or 75 μ m usually.The inventive concept set forth of disclosed method can also be applicable to form particle by minimum particle size less than the powder of above-mentioned representative minimum dimension (for example 0.001,0.01 or 1 μ m) in inventor's phase message.

For example can use screen set to measure particle mean size.For very trickle powder, can also analyze granularity with microexamination.For for example compressing tablet purpose, the flowability of above-mentioned powder is normally unsuitable.To be disclosed in for the illustrative methods of enough flowabilities of measuring material the detailed description of Fig. 9.

Therefore, " minuteness particle " or " fine content " is the particle that usually has the maximum sized individuality of particle mean size and 150 less than 100,50 or 20 microns, 100 or 75 μ m.

When several minuteness particles (for example 3,5,10 or more) coalescent and when forming the particle of full-size 150,100 or 75 μ m, they are called granule.To be called " acceptable particle " greater than above-mentioned maximum sized particle.Minuteness particle and/or granule are taken away rear those remaining particles by air stream be called " particle of acceptance ".

Low thrust can for example use the cylinder compacting machine to provide.The cylinder compacting machine can be furnished with optional being suitable for by the broken sieve of the thin slice (flake) of the material production particle that compresses or other device (for example oscillating mill or grindstone).If necessary, adopt the optional step of the broken sieve of thin slice or other device for the preparation of from other particle, separating minuteness particle and/or short grained material.

Therefore, by comprising that use applies thrust for generation of the method for the cylinder compacting machine of the ribbon (ribbon) of the powder that compresses to powder, described ribbon fragmentation can produce particle (for example by the thin slice disintegrating machine) usually.Thin slice disintegrating machine or similar device can make the high limit of size of particle controlled, for example by particle is sieved.The aperture size of the broken sieve of thin slice can be for example 0.5mm, 1.0mm or 1.2mm.

Can will hang down that thrust is transferred to minimum so as the powdered rubber that makes at least one of percentage, 5 percent, ten Percent or ten Percent five compress and/or classification step in become acceptable particle, and all the other materials are minuteness particle and/or granule.

If used thrust is too low, it may be too frangible for compressing tablet purpose for example that the inventor observes the particle accepted by described method.These particles also may be too large, for example greater than 3mm.Frangible particle can not flow or well for for example it is not enough firm for using in the compressing tablet process.

Can adjust maximum low thrust, so as with 75% or following, 70% or following, 65% or following, 50% or following or 40% or following powder be packed together to acceptable particle, and remainder remains minuteness particle and/or granule.Maximum low thrust is at most 500%, 250% or 150% of minimum low thrust usually.

For example, thrust can be enough low so that make 75% or the powder of following weight be packed together to the acceptable particle that has greater than the granularity of 150 μ m (and/or 100 μ m or larger average-size), and remainder still is minuteness particle and/or granule.

Certainly, minimum and maximum low thrust will depend on used concrete compacting machine and powder.Therefore, for example at Hosokawa ^TMIn (Osaka, Japan) Bepex Pharmapaktor L200/50P cylinder compacting machine, the low thrust of minimum can be adjusted, to be minimum possible thrust 15kN, 20kN or 30kN.At Hosokawa ^TMIn the Bepex Pharmapaktor L200/50P cylinder compacting machine, the low thrust of maximum can also be adjusted, to be 80kN or less, 70kN or less, 60kN or less or 45kN or less.

Low thrust is 60kN or less for example 45kN or less normally.Low thrust is 16kN or larger normally.

Can also adjust maximum low thrust and form solid bridge (for example because the described material of heating) in order in the particle of the material that obtains, there is no.Some compacting machines well known in the art provide and have cooled off the measure of the material that compresses in order to alleviate the heating problems of using high thrust to cause.Use method and system of the present invention, this precautionary measures are unwanted.

Can adopt the method that is suitable for used compacting machine to adjust thrust, for example be fed to feed rate in the compacting machine by control.

(for example induced-draught fan) provides air-flow in any suitable manner.Can make air-flow (for example air) directly pass grading room.Air-flow to some minuteness particles of major general and/or granule are separated from comprise the material that can accept particle, granule and minuteness particle.Isolated minuteness particle and/or the granule taken away in the air-flow can be transferred to for example cyclone separator (cyclone) of separator from grading room, in cyclone separator, carrier gas be told from minuteness particle and/or granule.Then, minuteness particle and/or granule can be sent back to be used for directly processing again (being about to its recirculation is used for compressing) in the system or can be placed on container and be used for processing again later on.

Therefore, utilize the equipment comprise grading plant can be easily minuteness particle and/or granule to be told the particle from can accepting.Just cater to the need, grading plant comprises grading room.

As discussing in more detail in an embodiment, it is usually larger than the largest particles that enters grading room dimensionally to accept particle from grading room maximum out.The inventor thinks and the coalescent process of granule and/or minuteness particle and larger particles has occured during by grading room transporting material.

In general, the direction of air current flow suitably has the component with the mobile opposite direction of the material that compresses (particle of especially accepting).The direction of common air current flow substantially opposite with the direction of the flow of matter of compression (for example about 150-180 °), and preferably opposite.

Gas can for example be air (being suitably dry air).

The minuteness particle that the device that the material that grading plant (means) can comprise device that steering current enters grading plant, make compression moves and guiding are carried from the air-flow that grading plant shifts out and/or granule for example are used for the device processed again.Can through Action of Gravity Field and/or mechanical device the material of compression be moved simply.

It is known going for implementing many grading plants of the present invention.Grading plant can for example comprise mobile device for example whirligig such as cylinder (or cone), and the material of compression is moved axially along it in air-flow.Can move with the gravity means material of compression, perhaps can or promote the movement of the material that compresses by device (for example cylinder) with mechanical means.Whirligig can comprise the structure of material of the compression of at least a guiding whirligig inside, for example helical structure.Passage or baffle plate that this helical structure can be moved by the material that guiding compresses consist of.The component that gravity is auxiliary or gravity is resisted can be provided by the axle of Sloped rotating device.

Advantageously, grading plant does not need to make the material of compression by any sieve (for example mesh screen).Sieve has the tendency of the broken slight material that compresses, and therefore, avoids the protected compressing tablet that for example is used for of particle (the favourable character with them) that uses sieve to make slight compression.And sieve is blocked easily, and this can interrupt flow process, especially when moving with continued operation.In addition, owing to instantaneous obstruction, the mesh size of sieve may change at run duration.

Grading plant can comprise the hole, by these holes minuteness particle and/or granule is carried away.In a specific embodiments of the present invention, air-flow enters whirligig (with the direction opposite with the movement of the material that compresses) vertically, and the hole on the whirligig sidewall (perforation) goes out from whirligig.

As mentioned above, grading plant can comprise the mobile device (for example whirligig) of the material that compresses in the mobile grading plant.Mobile device can comprise the hole, flows to and flows out mobile device through these gas flow holes, and through these holes minuteness particle and/or granule are carried away.Hole (air-flow by its flow out said apparatus) can be larger than the minuteness particle that can eliminate basically, for example be at least the particle accepted average diameter 50%, 100% or 150%.With absolute terms, described hole can for example have about 250 μ m, 500 μ m or 750 μ m or larger minimum dimension.This helps to prevent the obstruction in hole, even when the minuteness particle of the relative large volume that need to from the material that compresses, isolate the material that may adhere to.On this meaning, mobile device significantly is different from the air sieve of prior art, and in the air sieve of prior art, screen size must approximately have identical size with the superseded particle of maximum.From to depend on screen size different in the screening, grading plant of the present invention depends on air-flow carries away minuteness particle from mobile compression material ability.Can accept particle size determine be by their gravity of balance (and other power, for example mechanical force and centrifugal force) and with it the antagonism air-flow strength realize.

Grading plant and/or in air transporting arrangement since for example the alone or in combination impact of carrier gas air-flow, mechanical force, attraction and electrostatic force can make some minuteness particles and/or granule and other particles coalesce.Therefore, this process may produce the larger particle of particle that produces than the broken sieve of the thin slice of described system.In some embodiments, during classification, the agglomerated intensity of the material of compression may be significant.

Can make up to realize the movement of the material in the air-flow by application examples such as mechanical force, gravity, centrifugal force or its.In some embodiments, for realizing benefit of the present invention, may not need the Mechanical Moving assembly in the grading plant.In some embodiments, acceptable particle for example drops in the air-flow through action of gravitation, and unacceptable particle and particle are moved with at least part of opposite direction by air-flow.

The average residence time of material in grading plant that compresses normally at least 2 seconds, may in addition at least 5 seconds, although the grading effect (comprising any coalescent effect) of expectation can also be accomplished within the time shorter than the above-mentioned time.

The superseded part that it should still be noted that described material can also contain acceptable particle.By acceptable particle is recycled, make for example more efficient and easier maintenance of integral device, this is owing to can more easily be avoided the obstruction of grading plant.Can with the begin place of these particle deliveries accepted of eliminating to pelletization, be used from again processing with other material that is eliminated one.With regard to efficient, we preferably recycle maximum particles accepted of 30%, 45%, 60% or 75% with minuteness particle.The inventor does not observe any illeffects to particulate matter that is caused by recirculation.This is owing to using low thrust.

According to other feature of the present invention, we provide the device that comprises hold down gag and be suitable for by carry away minuteness particle and/or granule in air-flow (for example air) minuteness particle and/or granule are told from the material that compresses.

Therefore, can be characterised in that according to equipment of the present invention: the above-mentioned grading plant that for example comprises whirligig (seeing (401) in the accompanying drawing for example) contains at least one outlet opening (seeing (511) in the accompanying drawing for example), said flow flows out described device by this outlet opening, described outlet opening is enough large so that can make and have acceptable matter the particle of (for example mobile compressing tablet (tabletability), size, especially size) flows out described device.

Described equipment can also comprise separator (for example cyclone separator) so that air-flow and particle (removing) are separated from the material that compresses.

Another concrete aspect of the present invention provides dry granulation equipment, it is characterized in that the grading plant that this equipment comprises the hold down gag that can produce low thrust and is suitable for by carry away minuteness particle and/or granule in air-flow minuteness particle and/or granule are told from the material that compresses.This equipment can suitably comprise the cylinder compacting machine of the ribbon that produces the powder that compresses, and described ribbon then will be broken to produce particle.Described equipment can be characterised in that grading plant comprises the device of the mobile material that compresses.This device that moves the material of compression can comprise the device that moves the material of compression through gravity or mechanical means.Can for example be characterised in that according to equipment of the present invention described grading plant comprises the structure (seeing for example (403) of accompanying drawing) of at least a material for guiding the compression in the grading plant.

Can comprise the device that air-flow is provided according to equipment of the present invention, wherein the flow direction of air-flow has the component (for example the flow direction of the material of the flow direction of air-flow and compression substantially opposite) opposite with the flow direction of the material that compresses.

Usually be equipped with grading plant according to equipment of the present invention, this grading plant comprises whirligig (for example cylinder or cone, especially cylinder), and the material of compression axle along this whirligig in described air-flow moves.Utilize helical structure can help the material that compresses along the moving axially of whirligig, the material that described helical structure guiding compresses moves.Grading plant for example whirligig can contain porosely, and minuteness particle and/or granule are carried away through described hole.When expectation generated the particle of average-size x, described hole should have 0.5x or 1.0x or even the minimum dimension of 1.5x.With absolute terms, described hole can for example have the minimum dimension of 250 μ m, 500 μ m or 750 μ m.

The present invention also provides and be adapted to pass through the grading plant that carries away minuteness particle and minuteness particle and/or granule are told in air-flow from the material that compresses, this grading plant comprises whirligig for example cylinder or cone, make the material of compression mobile in described air-flow along the axle of this whirligig, and this whirligig contains porose, through this hole minuteness particle and/or granule is carried away.

In one embodiment, described grading plant comprises grading room, and open circles cylinder (or cone) is housed in this grading room.Described opening cylinder (or cone) rotatably can be supported on the roller bearing.Carrier gas is fed to opening cylinder (or cone) inside.Can punch at the cover of cylinder (or cone), through this hole minuteness particle and/or granule are carried away in carrier gas.As described in other places, the minuteness particle and/or the granule that are carried away can be caught to recycle.

In method and apparatus according to the invention, can use gas to transport.Suitably, be used for carrying away in gas and the continuous operations of minuteness particle of material of compression for transporting the carrier gas of material with fluid communication.

Therefore, suitably, will be transported to the device that applies thrust from the storage storehouse for the powder that compresses by device (comprise and use air transporting arrangement).

Gas is carried and can be used the device (for example cyclone separator) that separates carrier gas from minuteness particle.Described device for example should be able to be with the airflow rate continuous operations that approximately equate, meaning is for the carrier gas air-flow that uses in classification process variations (for example compression shock) interference that is not stressed, and is required as various types of filters are being opened.

In context " continuous operations " refer to can not need keep in repair or other interrupts running at least 1 hour, 8 hours or 24 hours.

One aspect of the present invention is the dry granulation material that contains the particle that the method according to this invention obtains.

According to the present invention, we also provide particulate matter, and wherein particle can have the average particle size particle size greater than 50,100,200 or 500 microns, 3,2 or 1 millimeters maximum particle size and good flowability.Described material selectively or additionally has at least a, two kinds, three kinds or four kinds of following character: in the particle substantially without the quite granule of ratio (substantial proportion) and/or minuteness particle (usually relevant with other particle), good compressibility (compressibility) and compressing tablet in the loose structure of interparticle solid bridge, good homogeney, particle, the particulate matter.Particle suitably has greater than 100 microns average particle size particle size and 3 millimeters maximum particle size.

In addition, not bound by theory, the inventor thinks that the friction electro ultrafiltration that is caused by system by powder affects the product of the inventive method.Think in the prior art for example when transporting by air-flow or in air-flow, moving, small-particle may have the trend that produces negative electrical charge, and larger particle has the trend (perhaps less at least negative electrical charge) that produces positive charge and (sees the article " generation of the two poles of the earth electric field during the industrial processing powder (Generation of bipolar electricfields during industrial handling of powders) " such as people such as Ion.I.Inculet, chemical engineering science (ChemicalEngineering Science), 61 (2006), page number 2249-2253).Therefore, according to of the present invention one embodiment of drafting, the particulate matter of dry granulation is provided, be characterised in that it contains usually have 50 μ m to the 3mm particle of average-size of (for example 100 μ m to 3mm), this particle is comprised of following part: (a) core of compacting, and it comprises the minuteness particle of the material (material) that is associated by Van der Waals force; (b) coated layer, this coated layer comprises minuteness particle and/or the granule of described material, and they are associated with the core of described compacting by electrostatic force.According to the embodiment that another is drafted of the present invention, the particulate matter of dry granulation is provided, be characterised in that it contains have 50 μ m to the 3mm particle of average-size of (for example 100 μ m to 3mm), this particle is comprised of following part: (a) core of compacting, and it comprises the minuteness particle of the material that is associated by Van der Waals force; (b) the coated layer of porous, it comprises minuteness particle and/or the granule of described material.In one embodiment, coated layer (b) mainly contains for example 70%, 80% or 90% minuteness particle, rather than granule.In another embodiment, coated layer (b) mainly contains for example 70%, 80% or 90% granule, rather than minuteness particle.

The core of compacting is suitably essentially no solid bridge.

The feature of described dried particulate matter can also be: the particle mean size of the particle of material is 1-100 μ m, the average-size of the core of compacting is 50-3000 μ m, and the ratio of the average-size of the minuteness particle of coated layer material and/or the core of short grained particle mean size and compacting is at least 1: 10, for example at least 1: 30.

Quite substantially there is not minuteness particle in the granule of ratio and the particulate matter in the loose structure of the normally good flowability of the character that particulate matter is expected most, good compressing tablet, good homogeney, particle, the particulate matter.

For the granularity of analysing particulates material, can use cover (for example 4 a) sieve, wherein the opening size of sieve is for example 850 μ m, 500 μ m, 250 μ m and 106 μ m.

Can calculate according to the geometrical mean of two adjacent screen openings diameters in the above-mentioned cover group particle mean size of the material that is graded device acceptance.

d _i＝(d _u×d _o) ^0.5

Wherein

d _iI in the=described cover group ^ThThe diameter of sieve

d _u=particle can (i be carried out in screening from the diameter of its opening that passes through ^Th)

d _o=particle can not be from the diameter (i of its opening that passes through ^ThSieve).

Because it is unpractical calculating separately each particle and calculating mean value, should calculate particle mean size according to weight.Can use-case such as following equation carry out above-mentioned calculating:

d _gw＝log ^-1[∑(W _i?log?d _i)/∑W _i]

Now can following calculating standard deviation:

S _gw＝log ^-1[∑W _i(log?d _i-log?d _gw) ²/∑W _i] ^0.5

The detailed description of exemplary dimensions analytical method shown here can " ScottBaker and Tim Herrman estimate granularity (Evaluating Particle Size), Kansas StateUniversity, in May, 2002 at paper." in find.

What should remember is when passing through the granularity of said method analysing particulates material, and at least some coated particle/granules are broken away from from the core of compacting.

Can use opening cone (for example filter tunnel) measurement flowing property, for example good flowability that have circular open at the narrower end of cone.One cover above-mentioned cone and relevant method of testing is described in the detailed description about Fig. 9.

Substantially refer to for example following structure without the solid bridge in grain structure, the particle that wherein on average is lower than 30% or 10% particle is kept together by the solid bridge.Can for example use the existence of solid bridge in the scanning electron microscope analysis grain structure.By described device, the single minuteness particle in the evaluation grain structure and visual solid bridge (for example structure of the crystallization between the particle of particle) should be possible.

In context, good homogeney for example can refer to by with the standard deviation of average particle size particle size less than 2.5, less than 2.25 or the particulate matter that forms less than 2.0 particle.The inventor believes that also the homogeneity characteristic of particulate matter can be realized by the loose structure of particle at least in part in the embodiment of the present invention.Because the homogeney of particulate matter can be transported particulate matter in the situation without any obvious material segregation in preparation process.In addition, the good homogeney of particulate matter can help the good compressing tablet of particulate matter, for example shows as not to be prone to push up to split phenomenon.

The structure of the particle of accepting (and especially coated layer) can be porous usually, namely may substantially not have dense granule in the particulate matter.Because using the core of low thrust expection particle is porous.The loose structure of particle can be optionally or is additionally referred to for example can to observe particle surface and comprise the granule of hole and/or loose binding and/or approximately at least 1,2 or 5 micron and be lower than 150,100 or 50 microns minuteness particle.For example see Fig. 2 d, 2e and 2f about the image of particle with loose structure.

Substantially refer to that without dense granule the substance weight that obtains less than 20% or 10% is dense granule.Dense granule for example is that its surface looks like fine and close, non-porous particle (seeing for example Fig. 2 c).

Particulate matter can also comprise granule and/or the minuteness particle of suitable ratio, and they may for example form the coated layer of loose binding at larger particle by electrostatic force.The suitable ratio of granule and/or minuteness particle can be greater than 2%, 5% or 10% of particulate matter gross weight.The particle of little preferred porous and/or the existence of minuteness particle can promote for example flowability and the compressibility of particulate matter energetically.This can make tablet by the compacting of described particulate matter have the tensile strength of improvement and/or disintegration time faster.Astoundingly, and with prior art (for example in WO99/11261) teach opposite, quite the granule of ratio and/or minuteness particle seem usually can not affect in any significant bad mode the flowability of particulate matter in the particulate matter of the present invention.

The inventor also finds (at least in some cases): if will take away through the particle that the inventive method obtains, and return and to add (for example maximum 15% minuteness particle being returned and be added in the particulate matter by the molecular starting material of microfine of certain ratio, this particulate matter can contain for example 20% minuteness particle and/or granule, material such as " mobile embodiment 3 "), so do not affect homogeney, flowability and the compressing tablet of particulate matter in obvious bad mode.The minuteness particle that adds may be introduced in the porous surface of the particle that is formed by the inventive method.Therefore, the inventor thinks in some embodiments, can be with the particle of embodiments more of the present invention as " carrier granular ", should " carrier granular " can suck maximum 10%, 20%, 30% or more minuteness particle and/or granule, for example be drawn in the particle hole, these minuteness particles and/or granule comprise the material identical or different with carrier granular.The flowability of said mixture can be on good, very good or good level.

Think that described particulate matter has good compressibility, because extremely less granular surface is porous.The compressibility of particulate matter of the present invention can be good, and namely it can have the Hausner ratio greater than 1.15,1.20 or 1.25.Can adjust low thrust of the present invention so that as remain on good level with the represented compressibility of Hausner ratio.

Can use formula p _Tap/ p _BulkCalculate the Hausner ratio, wherein p _TapRepresent the real bulk density of pier of particulate matter, and p _BulkRepresent the loose bulk density of particulate matter.Can calculate bulk density by the 50mg particulate matter being poured in the glass cylinder (for example using FORTUNA, model 250:2ml) with 3.8mm internal diameter.After being poured into particulate matter in the cylinder, observe the volume of particulate matter and the loose bulk density of count particles material from the scale of glass cylinder.In order to measure the real bulk density of pier, use and highly fall suitable power from 5cm with glass cylinder pier 100 times on the table.Observe the volume of the particulate matter of pier reality and the real bulk density of the pier of count particles material from the scale of glass cylinder.

Astoundingly, and with prior art (for example in WO99/11261) teach opposite, the compressibility of particulate matter of the present invention does not show any harmful effect to the particulate matter flowability usually.For example, the particulate matter that has an embodiment of the present invention that is higher than 1.25 Hausner ratio shows very good or good flowing property usually.

In pharmaceuticals industry, usually need porous, mobile good particle, for example because the tablet that is improved by the particle manufacture of porous is possible.Described tablet for example can be than the significantly quickly disintegration of tablet by the dense granule preparation.In addition, the tablet by the porous particle compacting shows usually than the higher tensile strength of tablet by the dense granule compacting.For tablet, high tensile strength normally needs, because this type of tablet is than the easier packing of frangible tablet and transportation.

But particulate matter can be compressing tablet, so that Application standard pressed-disc technique (for example adopting the available compression force of tablet press machine of extensive use), it is possible described particulate matter being formed have the tensile strength of at least 5N, 10N or 15N.Can for example use MECMESIN ^TM(Mecmesin Limited, West Sussex, UK) and the measurement mechanism of model BFG200N are measured tensile strength.

Particulate matter can comprise available excipient at least a API and/or at least a pharmaceutical preparation.In one embodiment, particulate matter comprises (for example consisting of) at least a (as a kind of) API.In another embodiment, particulate matter comprises at least a (as a kind of) API and at least a (as a kind of) excipient.

Therefore, the present invention also provides the method for preparing tablet, and the method comprises compacting according to the particulate matter of dry granulation of the present invention, and this particulate matter is optional and one or more other mixed with excipients.Described one or more other excipient generally include for example dolomol of lubricant.The tablet that obtains by said method is another aspect of the present invention.

According to another feature of the present invention, we provide the tablet of the particle that comprises dry granulation.The feature of this tablet is: the particle that this tablet does not have the solid bridging to connect in the particle that forms tablet substantially.Perhaps or additionally, this tablet can have at least two or three following character: the lubricant of high tensile strength, high medicine carrying capacity, low amount, fast disintegration time and insensitive to period of storage.

Period of storage insensitive for example can finger tablet compared with new tablets after storing 4 months under 40 degrees centigrade and the 75% relative humidity condition, and the weight increase of tablet is lower than 2.0%, 1.5% or 1.0%.

High medicine carrying capacity refers to that tablet for example can comprise at least 40%, 60% or 80% API (s) of tablet total weight amount.

In the time of in tablet being put near the water of body temperature (namely 37 degrees centigrade), fast disintegration time can be to be less than 600,120 or 30 seconds.

As what can see in an embodiment, the tablet of the present invention with high tensile strength still can fast disintegration in water.

The high tensile strength of tablet can be greater than 100N, 60N, 30N or 15N, for example uses MECMESIN ^TMThe BFG200N measurement device.

The lubricant of low amount can be to be less than 1.0%, 0.5%, 0.3% or 0.2% of tablet weight.Frequent tensile strength, disintegration time and/or the dissolution time to tablet of greasing substance (for example dolomol) has adverse influence and is being known in the art.When lubricant was mixed with the particle of prior art, greasing substance can for example tend to form film around (densification) particle.This film can stop form between the particle during the compressing tablet suitable bonding.(see the paper " the fixed adhesive matrix model (A coherent matrix modelfor the consolidation and compaction of an excipient with magnesiumstearate) with compressing that contains the excipient of dolomol " such as people such as K.A.Rietma, International Journal of Pharmaceutics, 97 (1993), page number 195-203).Therefore, particle of the present invention is used tensile strength and the disintegration time that can help energetically tablet of the lubricant of low amount.The inventor infers the possible soft of particle of the present invention and surface porous can prevent the formation of above-mentioned film, because particle may have larger, more rough surface that can utilize for the lubricant of coupling.Therefore, can further improve the character of the tablet that obtains.

Lubricant mainly can be distributed in the porous surface of the particle of tablet.Lubricant can for example mainly be arranged in the surface of the particle that forms tablet and the hole on surface, and the in-core of particle without or almost do not have a lubricant.Lubricant can be distributed, and for example so that greater than 90%, 80% or 70% lubricant is positioned on 10%, 20% or 30% the cross section (tangent plane) that is lower than the total section of tablet.Can be with for example comprising SEM and can identifying that the system of other device of the particle that particularly contains lubricant material observes the position of lubricant particle on the tablet section.

The hydrogen bond liquid that tablet can suitably have significantly low percentage is water for example.

Tablet suitably has liquid and/or the hydrogen bond of significantly low percentage, lubricant is distributed in tablet unevenly, and tablet also has at least two kinds of character in the following character: fast disintegration time, high tensile strength, high medicine carrying capacity and the lubricant of low amount.

Tablet of the present invention can comprise the excipient of the starch that contains dry granulation.For example it can comprise excipient, and described excipient contains at the most the starch of 60% dry granulation.

Particulate matter of the present invention or tablet can comprise at least a active pharmaceutical ingredient of minimum 1%, 5% or 10% (weight) and maximum 100%, 95%, 90%, 80% or 70% usually.In some embodiments, described powder contain at least 60% active pharmaceutical ingredient of amount of (for example at least 80%).Particulate matter or tablet can comprise at least a excipient of minimum 5%, 10%, 20% or 30% (weight) and maximum 99%, 95% or 90%, for example long-chain polymer such as starch or cellulose in addition.

For disintegration and the dissolution time of controlling tablet of the present invention, for example methylcellulose (metholose) or the Hydroxypropyl methylcellulose (hydroxypropyl methylcellulose) of maximum 90%, 70% or 50% (weight) can be joined in the preparation.The dissolution time of described tablet in body of stomach system can be at least 1,4,8 or 12 hour.

For example comprising, the stripping pattern of the preparation of Hydroxypropyl methylcellulose can be for example following: after about 2 hours, discharge the API (s) of about 12%-about 60%; After about 4 hours, discharge the API (s) of about 25%-about 80%; After about 8 hours, discharge the API (s) of about 50%-about 100%; After about 12 hours, discharge the API (s) greater than about 75%.

For the fast disintegration time of the tablet of at least a active pharmaceutical ingredient of realizing comprising at least 5%, 20% or 30% (weight), tablet can also comprise minimum 1%, 3% or 5% and the disintegrant of maximum 7%, 10% or 20% (weight).In some embodiments, the percentage of the disintegrant in the tablet can also be higher than 20%.Disintegrant for example can be some starch or carboxymethyl cellulose (CMC, for example Nymcel ^TM) or their combination.Particulate matter or tablet can also comprise minimum 1%, 5% or 10% and the filler (diluent) of maximum 60%, 80% or 94% (weight) microcrystalline cellulose for example.Can use method of the present invention that API, disintegrant and filler are granulated together or separately.

In order to improve for example taste of rapid disintegration tablet (Orally disintegrating tablet), maximum sweeteners of 50%, 70% or 90% (for example xylitol) can be included in the tablet.If necessary, sweetener can be used the embodiment of the inventive method to granulate.In addition, sweetener can be granulated separately or with at least a other formulation components (API or excipient).We observe at least for some APIs, compare with the tablet that other component is granulated with sweetener wherein, use the sweetener (xylitol) of granulating separately can cause faster release time in tablet.

Tablet of the present invention can have good content uniformity.For example, the standard deviation of tablet weight can be to be lower than 3.0%, 2.0% or 1.0% of tablet average weight.

In pharmacy, chemistry and food industry, method of granulating of the present invention and equipment go for many purposes.Described method and apparatus forms the particle of desirable properties with low thrust and air-flow.Thrust can be adjusted so that substantially avoid introducing the solid bridge in compaction step.The method and equipment be suitable for treatment product particle leniently with avoid making its fragmentation, from can accept to separate the particle minuteness particle and/or granule and randomly the material eliminated of recirculation in order in system, process again.Described equipment and method can easily be adjusted, control, but and more or less are continuous operations.

Can real-time analysis by size distribution and/or the flowability of the particle of described device fabrication, and can be according to the size distribution of this analysis and regulation particle.For example, the broken sieve of thin slice (seeing following Fig. 1 a and 1b) just can be so, can change pore size for the mesh screen of thin slice fragmentation by using some regulating measures.Another adjustable parameter is the gas flow rate of grading plant normally.

Because described method is processed superseded material again, in fact not waste so it can be economical, and can be suitable for providing the fast processing of a large amount of materials.Equipment of the present invention can be easy to clean and install, and method can be stable and predictable, therefore makes it be easy to control.

Because the homogeney of the particle that for example obtains and/or flowability can be avoided and the relevant problem of emanating.Method of the present invention can be used on a small scale and large-scale the application.Therefore, when under laboratory condition during a kind of product of develop (particle or the tablet that for example contain API (s)), the time that setting up the large-scale producing method of empirical tests needs can lack very much.

Because the method and apparatus of native system can be granulated various powder (comprising those that are comprised of 100% APIs); so can become particulate matter by independent material production in the pelletization separately; and after it is granulated separately, the particle that obtains is mixed.Before mixing API and the independent granulation of excipient may be had benefit, for example when raw material has significantly different granularities.

Can prepare different types of finished product by described particulate matter, comprise tablet, oral suspensions and capsule.

According to the present invention, we also provide the method for preparing tablet, and the method comprises the particle compressing tablet that maybe will use the inventive method to produce particle compressing tablet according to the present invention.

We have found that the inventive method can be for the production of the particle of the various powdered rubbers that can use in pharmaceuticals industry.

Therefore, the inventive method can be suitable for by the material production of the APIs that comprises one or more types particle of the present invention and tablet, and described APIs type comprises for example material of alexipyretic, antalgesic, antiphlogistic, hypnotic and sedative, antihypnotic, antacids, digestant, cardiotonic drug, antiarrhythmics, antihypertensive, vasodilator agent, diuretics, anti-ulcer agent, antiflatulent, osteoporosis therapy agent, antitussive, expectorant, antiasthmatics, antifungal, urinate improvement medicine, refreshment medicine, vitamins and other oral administration.APIs can use separately, and perhaps two or more APIs can unite use.

The inventive method can also be applicable to by the material production that comprises specific APIs particle of the present invention and tablet, and described specific APIs for example is paracetamol; acebutolol; melbine; Prozac; aspirin; aluminium aspirin; paracetamol; Ethenzamide; sazapirin; salicylamide; the lactyl phenacetin; isothipendyl; Diphenylpyraline; diphenhydramine; difeterol; triprolidine; Tripelennamine; Thonzylamine; Fenethazine; first ground piperazine; the diphenhydramine salicylate; carbinoxamine diphenyl disulfonate; alimemazine tartrate; the diphenhydramine tannate; the Diphenylpyraline 8-Chlorotheophyline; the mebhydrolin napadisilate; fenazil methylenedisalicylic acid salt; carbinoxamine maleate; chloroaniline dl-maleate; chloroaniline d-maleate; difeterol phosphate; alloclamide; Cloperastine; pentoxyverine (carbetapentane citrate); tipepidine; dextromethmorphan hydrobromide; dextromethorphan phenolphthalein hydrochlorate (phenolphthalinate); the tipepidine hibenzate; the Cloperastine fendizoate; codeine phosphate; Dihydrocodeine phosphate; coscopin; dl-methylephedrine saccharin salt; orthocoll; gualfenesin; caffeine; Caffeine Anhydrous; vitamin B1 and its derivative; vitamin B2 and its derivative; vitamin C and its derivative; aurantiamarin and its derivative and salt thereof; vitamin B6 and its derivative; and niacinamide; calcium pantothenate; Glycinates; magnesium silicate; synthetic aluminium silicate; synthetic Hydrotalcite; magnesia; aluminum glycinate; aluminium hydroxide/bicarbonate aluminium coprecipitate; aluminium hydroxide/calcium carbonate/magnesium carbonate coprecipitate; magnesium hydroxide/alum coprecipitate; magnesium carbonate; Almasilate (magnesium aluminometasilicate); ranitidine; Cimetidine; famotidine; naproxen; Diclofenac; piroxicam; azulenes; Indomethacin; Ketoprofen; brufen; difenidol; fenazil; meclozine; dramamine; the Fenethazine tannate; the diphenhydramine fumarate; scopolamine hydrobromide; Oxyphencyclimine; bentyl; methixene; Methylatropine Bromide; octatropine methylbromide; scopolamine methylbromide; Methylbenactyzium Bromide; belladonna extract; isopropamide iodide; papaverine; amino benzoic Acid; cesium oxalate; aminophylline; diprophylline; theophylline; ISDN; ephedrine; cefalexin; the ampicillin; ulcerlmin; allyl isopropylacetyl urea; other pharmacy activity component of any suitable (other) the pharmaceutically acceptable acid of Bromovalerylurea and its or base addition salts (for example those salt commonly used) and description in European Pharmacopoeia (third edition) and a kind of; the combination of two or more described active components.

The inventive method can also be applicable to by the material that comprises solid APIs (this APIs is insoluble in water) production particle of the present invention and tablet, and described APIs is antipyretic-antalgic agent such as benzoic acid for example, quinine, calcium gluconae, dimercaprol, sulfoamide, theobromine, riboflavin, Mephenesin, phenobarbital, thiacetazone, Quercetin, rutin, salicylic acid, veramon (pyrabital), irgapyrin, foxalin, griseofulvin, phenacetin, drugs for nervous, the sedation anesthesia medicine, muscle relaxant, hypotensor, antithistamine, antibiotic (acetyl spiramycin for example, erythromycin, kitasamycin, chloramphenicol, nystatin, colistin sulfate), steroid hormone class (methyltestosterone for example, progesterone, Oestradiol benzoate, ethinyloestradiol, desoxycorticosterone acetate (DOCA), cortisone acetate, hydrocortisone, prednisolone), non-steroidal vitellogenic hormone (dienestrol for example, diethylstilbestrol, Chlorotrianisene), other liposoluble vitamin and the pharmaceutically acceptable acid of its suitable (other) or base addition salts (for example those salt commonly used) and other pharmacy activity component of in European Pharmacopoeia (third edition), describing and a kind of, the combination of two or more described active components.

Active pharmaceutical ingredient can for example be selected from Acebutolol, Fluoxetine hydrochloride, paracetamol, sodium vedproate, Ketoprofen and Metformin hydrochloride.

The inventive method can also be applicable to by comprising the excipient that for example can use or material production particle of the present invention and the tablet of other composition in pharmaceuticals industry, and described excipient or other composition for example are l-aspartic acid, wheat gluten (wheat gluten powder), gummi arabicum pulveratum, alginic acid, alginates, alphalise starch, ethyl cellulose, casein, fructose, dry ferment, dry gel aluminum hydroxide, agar, xylitol, citric acid, glycerine, gluconic acid sodium salt, Glu, clay, cross-linked carboxymethyl cellulose sodium, Nymcel ^TMSodium carboxymethylcellulose, Crospovidone, calcium silicates, cinnamomi cortex pulveratus, avicel cellulose-carmethose, synthetic aluminium silicate, wheaten starch, rice starch, potassium acetate, CAP, Dihydroxyaluminium Aminoacetate, 2,6-dibutyl-4-methylphenol, dimeticone, tartaric acid, potassium hydrogen tartrate, magnesium hydroxide, calcium stearate, dolomol, Refined shellac, the sucrose of purifying, D-glucitol, skimmed milk power, talcum powder, the L-HPC of low degree of substitution, dextrin, pulverous bassora gum, calcium lactate, lactose, sucrose, farina, L-HPC, Hydroxypropyl Methylcellulose Phathalate, glucose, partially pregelatinized starch, pullulan, pulverous cellulose, pectin, polyvinylpyrrolidone, maltitol, maltose, PEARLITOL 25C, Lactis Anhydrous, calcium phosphate dibasic anhydrous, anhydrous calcium phosphate, Almasilate, methylcellulose, aluminum monostearate, glycerin monostearate, Arlacel-60, carbo medicinalis, the graininess cornstarch, dl-malic acid and possible other material that is categorized as excipient in handbook of pharmaceutical excipients (the Handbook of PharmaceuticalExcipients) third edition of Arthur H.Kibbe and a kind of, the combination of two or more above-mentioned excipient.

Method of the present invention goes for by the material production that comprises disintegrant particle of the present invention and tablet, and described disintegrant for example is carboxymethyl cellulose, Nymcel ^TMSodium carboxymethylcellulose, cross-linked carboxymethyl cellulose sodium, cellulose (for example hydroxy propyl cellulose of low degree of substitution), starch (sodium carboxymethyl starch for example, hydroxypropul starch, rice starch, wheaten starch, farina, cornstarch, partially pregelatinized starch) and in handbook of pharmaceutical excipients (the Handbook ofPharmaceutical Excipients) third edition of Arthur H.Kibbe, be categorized as other material of disintegrant and a kind of, the combination of two or more above-mentioned disintegrants.

Method of the present invention goes for by the material production that comprises adhesive particle of the present invention and tablet, and described adhesive for example is synthetic polymer such as Crospovidone; Carbohydrate is such as sucrose, glucose, lactose and fructose; Glycitols is such as sweet mellow wine, xylitol, maltitol, antierythrite, sorbierite; Water-soluble polysaccharide, for example cellulose such as avicel cellulose, microcrystalline cellulose, cellulose powder, hydroxy propyl cellulose and methylcellulose; Starch; Synthetic polymer is polyvinylpyrrolidone for example; Inorganic compound, for example calcium carbonate; With other material that in the handbook of pharmaceutical excipients third edition of Arthur H.Kibbe, is categorized as adhesive; And combinations a kind of, two or more above-mentioned adhesives.

The example of fluidizing reagent comprises silicon compound for example Silicon dioxide, hydrate, light (light) silicic acid anhydride and be categorized as other material and the combination a kind of, two or more above-mentioned fluidizing reagents of fluidizing reagent in the handbook of pharmaceutical excipients third edition of Arthur H.Kibbe.

According to a further aspect in the invention, we provide particulate matter, but it is characterized in that described material is compressing tablet, and have good flowability, and this material comprises at least 10% at least a following drug ingedient:

-Acebutolol,

-Fluoxetine hydrochloride,

-paracetamol,

-sodium vedproate,

-Ketoprofen and

-Metformin hydrochloride.

According to a further aspect in the invention, we provide tablet, the tensile strength that it is characterized in that described tablet is 10N at least, and tablet is that described particle comprises at least a following active pharmaceutical ingredient of at least 10% (weight) by the particle preparation of dry granulation:

-Acebutolol,

-Fluoxetine hydrochloride,

-paracetamol,

-sodium vedproate,

-Ketoprofen and

-Metformin hydrochloride.

According to a further aspect in the invention, we provide the tablet that forms by the compressed dry particulate matter, described particulate matter comprises 60% or more (for example 70% or 80% or more) active pharmaceutical ingredient, and described active pharmaceutical ingredient is selected from paracetamol, Metformin hydrochloride, Acebutolol and sodium vedproate.The excess of the composition of the particulate matter of doing can for example be one or more disintegrants, and this disintegrant is selected from starch, cellulose and cellulose derivative.According to a further aspect in the invention, we provide the tablet that forms by the compressed dry particulate matter, described particulate matter comprise (i) contain 80% or more (for example 90% or more as 100%) the particle of active pharmaceutical ingredient, described active pharmaceutical ingredient is selected from paracetamol, Metformin hydrochloride, Acebutolol and sodium vedproate; (ii) comprise the particle that one or more are selected from the disintegrant of starch, cellulose and cellulose derivative.In arbitrary situation of above-mentioned two situations, dried particulate matter is pressed into tablet before, can randomly lubricant be mixed with this particulate matter.

In some embodiments, tablet near body temperature namely in 37 ℃ the water less than 60 seconds with regard to disintegration.For quickly disintegrated tablet, API is suitable for being no more than 95% of tablet composition, and said composition comprises at least 2% disintegrant.The suitable tensile strength that has greater than 40N of tablet.In one embodiment, tablet can contain 90% or the xylitol of amount still less.

Embodiments more of the present invention are described in the literary composition, and other application of the present invention and to revise for those of ordinary skill in the art be apparent.

Accompanying drawing describes in detail

Hereinafter, explain the present invention with reference to accompanying drawing, but never be restriction the present invention, wherein

Fig. 1 a and Fig. 1 b show according to embodiments of the present invention example devices,

Fig. 2 a shows the according to embodiments of the present invention application of cylinder compacting machine,

The application that Fig. 2 b demonstration cylinder compacting machine is produced the porous particle of evitable densification (according to prior art) and expectation,

Fig. 2 c shows the example of the particle of producing with art methods,

Fig. 2 d shows the example according to the particle of embodiment of the present invention,

Fig. 2 e shows another example according to the particle of embodiment of the present invention,

Fig. 2 f shows the another example according to the particle of embodiment of the present invention,

Fig. 2 g illustrates the example relevant with the formation of the particulate matter of embodiment of the present invention,

Fig. 2 h shows the particle size distribution figure of the material shown in Fig. 2 g,

Fig. 2 i shows the surface image of the particle that produces according to the different low compression Lik-Sangs of embodiment of the present invention use,

Fig. 3 shows the exemplary hierarchical device according to embodiment of the present invention,

Fig. 4 shows the exemplary hierarchical device, and it comprises the other whirligig that can use according to embodiment of the present invention,

Fig. 5 a and Fig. 5 b show two the alternative exemplary barrel assemblies that can use in grading plant shown in Figure 4,

Fig. 5 c shows exemplary steel plate with holes, and it can be used as the according to embodiments of the present invention parts of whirligig,

Fig. 6 shows the exemplary twinfilter configuration (arrangement) that can make according to embodiments of the present invention system's continuous operations,

Fig. 7 shows the exemplary configuration that is used for detecting and adjusting in real time the character of the particle of accepting,

Fig. 8 shows the exemplary configuration of the particulate matter that is used for the independent material that compresses of mixing, and

Fig. 9 shows the exemplary means that is used for measuring powder or particulate matter flowability.

Accompanying drawing describes in detail

The equipment 100 of embodiment of the present invention (Fig. 1 a and 1b) comprises hold down gag (it is pressed into particle with powder material) and grading plant (it is separated at least some minuteness particles and/or granule from can accepting particle).Two kinds of different alternativeses that in Fig. 1 a and 1b, show grading plant.Grading plant 112 among Fig. 1 a is showed in greater detail in Fig. 3.Grading plant 113 among Fig. 1 b is showed in greater detail in Fig. 4.The equipment that shows among Fig. 1 a and Fig. 1 b comprises raw material feed containers 101, and material to be granulated is fed in this container.Feed containers is connected with gas transmission pipeline 102, and material is sent to this gas transmission pipeline through feeder valve 103.The conduit of gas delivery system has the diameter of about 47mm, and their material for example can be some suitable plastics, for example polyethylene.The feeder valve can be so-called star clack valve.A kind of this type of clack valve is by the Italian pharmaceutical device production CO.RA of company ^TM(Lucca, Italy) produces.In running, can be with the closure member of valve alternatively with either direction Rotate 180 °, thus can avoid the accumulation of powder material in container.Can also use other to be intended to device with the powder material continuous feed, for example compartment feeder.

Can be transferred to the stream pressure in the conveying device 102 lower than environmental pressure.This for example can realize with induced-draught fan 104.Induced-draught fan is by BUSCH ^TM(Maulburg, Germany) preparation, model is Mink MM 1202 AV.This blower fan is for example operated at 1860 RPM.Can provide make-up carrier gas by connector 105.To be transported to the separator 106 through conveying device 102 from the material of feed containers feeding, separate from carrier gas with superseded minuteness particle with from the new charging of container 101 therein.This blower fan can be furnished with filter (shown in Fig. 6), and this filter bits is in the separator next door.Described device can continuous operations.A kind of this device is cyclone separator.After separating step, the powder of separation drops in the intermediate receptacle 107.

Container 107 can be contained on the LOAD CELLS 108 in order to measure the weight of material.Intermediate receptacle 107 is equipped with valve 109, and valve 109 can be identical with feed containers valve 103 types.Powder is transferred to hold down gag (for example the cylinder compacting machine 110) to produce the ribbon of the material that compresses from middle container 107, then this ribbon is sent to the broken sieve 111 of thin slice, produce particle by broken ribbon herein.Whether in the context of the present invention, use bolter or lapping device 111 all to think and compress is the step that produces the method for particle to be fractionated.Can be for example the thickness of rotating speed, the pressure of cylinder that is applied to hold down gag and/or the ribbon that obtains of cylinder of feed rate, cylinder compacting machine by changing powder material adjust the thrust of compacting machine 110.The thrust that this compacting machine can be applied is transferred to low-level so that the desirable properties of the material that obtains compressing, the porous of the particle that for example obtains and/or minuteness particle and/or short grained ratio.The broken sieve of compacting machine and thin slice is to well known to a person skilled in the art device.Behind hold down gag and thin slice breaker, partial material is particle form, but partial material will remain minuteness particle and/or short grained form.The full-size of particle and the average-size of particle for example can be subjected to, and the screen size of the broken sieve of thin slice affects.Yet, should be understood that because in the classification of described method and/or transport coalescent in the step, particle size can increase.

(show in the drawings) that in some embodiments equipment 100 can comprise a more than hold down gag (for example cylinder compacting machine) to improve for example capacity and/or the continuous working ability of equipment.Hold down gag may need some periodically to keep in repair interruption, for example in order to clean.Even equipment 100 one of can the continuous operations hold down gag is just keeped in repair.

The product of above-mentioned steps is transported to grading room 112, and this product comprises the particle of minuteness particle and porous, and this product can be static electrification lotus (for example through frictional electricity).One or two for example material the flowing to grading plant of star clack valve to control compression can be arranged between hold down gag and grading plant.How differently to be subject to flowing into the impact of the carrier gas stream of grading plant according to the particle of particulate matter, grading plant is divided into receiving portion and superseded part with particulate matter.Eliminate part and transfer to feed conveying device 102 for again processing with charging carrier gas air-flow, and the part that will accept directs in the product container 113.In this way, treatment product particle leniently, and will mainly comprise minuteness particle and/or short grained relatively a large amount of material is removed from described material.

The running of grading room 112 is described in more detail with reference to Fig. 3-6.There are many alternative grading plants.

In the embodiment shown in Fig. 1 a and Fig. 1 b, LOAD CELLS 108 is disposed at container 107.Sensors with auxiliary electrode were and Other Instruments are also configurable in other container and assembly of system.Do not have with all possible instrument displays in the accompanying drawings.If necessary, for example air transporting arrangement can assemble at least one differential pressure pickup 114, from the Information Availability of this sensor in the running of control appliance.

The present invention can also finish with batch process, at this moment, does not use immediately conveying device 102 to make superseded part turn back to system, but is mounted in the container of eliminating material.Do not describe this system in detail, but its structure and purposes will be very apparent to those skilled in the art.

By will be from various sensors differential pressure pickup 114, LOAD CELLS 108 and valve 103 information of collecting and be sent to control module about the information of the speed of rotation and motor load for example, and by well known to a person skilled in the art that mode uses suitable control logic and control loop, can make described equipment automatization.The thrust control of hold down gag (for example cylinder compacting machine) is useful especially, because grain structure and minuteness particle and/or short grained ratio are affected by used thrust obviously.Thrust depends on many parameters, for example the feed rate of the rotating speed of cylinder and powder material.For example, for specific drum rotation speed, the feed rate of powder material is faster, and thrust will be higher.

The material of conveying device 102 can be for example PVC, for example FDA PVC.Each assembly of system can be connected together with the electric wire that is used for ground connection.Suitably, whole system is ground connection.

In Fig. 2 a, cylinder compacting machine 200 uses and applies mechanical force and be pressed into ribbon 204,205,206 to the material 203 that the cylinder 201,202 of material to be compressed will contain raw material and the optional particle that recycles from grading plant.Particle 204 to be compacted into, 205 amount of substance are according to being applied to the thrust of material and the thickness of ribbon changes.In the middle of ribbon, remaining material 206 can keep the appearance of granule and/or minuteness particle.Granule and/or minuteness particle can not form separately can accept particle.Yet the existence of above-mentioned substance is to the classification of described method and/or transport the formation that can accept particle in the step and have energetically facilitation, for example by frictional electricity and electrostatic force.Minuteness particle and/or short grained ratio can change according to charging and thrust parameter (for example thickness of ribbon).

The mode that makes things convenient for of Adjustment System operating parameters is that thrust with the cylinder compacting machine is set to minimum (producing at least some particles) and the rotating speed of grading plant is set to ROTAB ^TMThen available maximum (for example about 100 RPM) in the device of the model 400EC/200 of (Warren, MI, USA) is adjusted flow rate of carrier gas so that have the particle accepted of expectation flowing property and is begun outflow system.Air-flow in the grading plant is too little to cause minuteness particle and/or the increase of short grained ratio in the particulate matter of accepting, and the air-flow that uses causes too greatly the particle accepted of large ratio unnecessarily to be processed again.For example by the flowing and the real-time measurement of the character of these particles of particle that adopt to accept, best air-flow can be set manually or automatically.A kind of described measurement configuration is presented among Fig. 7.

Fig. 2 b illustrates when using high thrust of the prior art and generates unwanted dense granule and/or have the particle 210 of solid bridge, 211 example.Have more dense granules in material, the quality of material is poorer for compressing tablet.Although using the flowing property of the material that the high thrust (or repeatedly compress with hanging down thrust) of prior art obtains also may be acceptable even without classification, but for some materials, the compressibility of described material and/or compressing tablet may be that some other characteristics that be on duty mutually or tablet (for example disintegration time) may not expected.And, in the compaction step of prior art method of granulating, can observe the remarkable heating of material, this for example causes and forms solid bridge and/or the degraded of grain fraction or the character of not expecting of particulate matter through crystallization.In addition, use high thrust usually to reduce the granule in the particulate matter that obtains and/or transport the step small particles and

Fig. 2 c shows cornstarch (CERESTAR commonly used in the prior art dry granulation method ^TMProduction code member C ^*Gel 03401, lot number SB4944) uses SEM (SEM) picture of the exemplary fine and close corn starch granules that high thrust (greater than 80kN, for example adopting Hosokawa Bepex Pharmapaktor L200/50P cylinder compacting machine) produces.

Fig. 2 d shows the picture of the exemplary porous-starch particle of the same starch that uses according to an embodiment of the present invention low thrust (in this example, 30-35kN adopts same Hosokawa cylinder compacting machine) and then use air current classifying production.For different materials, producing the dense granule of " the low thrust " of porous particle and the unacceptable amount of generation and/or have " the high thrust " of solid bridge particle can be different.We observe the particle surface of Fig. 2 c not as Fig. 2 d particle porous (namely finer and close).Have between the single particle than the dense granule of Fig. 2 c between the single particle of the porous particle of Fig. 2 d and more many free space (being the hole).Seem also to have on the dense granule surface than Fig. 2 d on the porous particle surface of Fig. 2 d the loosely connected particle of larger ratio.In addition, the particle of Fig. 2 c has more edge than the particle of Fig. 2 d.Porous particle round-shaped helps to contain the good fluidity of the particulate matter of this type of particle.The compressibility of particle can be improved in the lip-deep interparticle hole of porous particle shown in Fig. 2 d.

Fig. 2 e shows another embodiment of particle of the present invention.A large amount of 100% paracetamol particles 251 that image 250 shows with the device fabrication of embodiment of the present invention.In method of granulating, use the thrust of 60kN.According to our observation, can use than the higher thrust of other material of great majority paracetamol is granulated.Unless specify in addition, in the method with the following example in the grading plant described among the grading plant that uses and the Figure 4 and 5 c similar.The typical sizes of particle 251 is 500 to 1000 μ m in this sample.Image 252 shows the amplification picture on the surface of a described particle.The surface 254 that can observe the compression of particle from image 252 is mainly covered by granule 255 (for example about 5 μ m-50 μ m).Also the single granule 257 with this type of is presented in the image 256.Granule 255 relative looselys are connected on the particle 251, form the porous surface of this particle.Therefore, although the thrust height more used than typical material that uses, the surface that can observe truly the particle that obtains is porous.The inventor infers that the electrostatic force granule and/or the minuteness particle that generate by for example frictional electricity can be connected on the larger particle in the classification step of the method.The inventor infers that also the porous surface that passes through loosely connected granule formation on the particle surface of accepting can have significant active promoting function to flowability and the compressing tablet of particulate matter.

Fig. 2 f shows another embodiment of particle of the present invention.Image 260 shows a large amount of excipient granule 261 that comprises 70% microcrystalline cellulose and 30% cornstarch.In pelletization, use the thrust of 16kN.The typical sizes of particle 261 is 500 to 1000 μ m in this sample.Image 262 shows the amplification picture on the surface of a described particle.The surface that can observe the compression of particle from image 262 is covered by granule and/or minuteness particle 263 (for example about 5 μ m-100 μ m).Also described single granule 265 and single minuteness particle 266 are presented in the image 264.Granule 265 is connected on the particle 261 with minuteness particle 266 relative looselys, forms the porous surface of this particle.The ratio of granule (in this example, less than the particle of 106 μ m) is about 20%.The flowability of observing material is good.

Fig. 2 g illustrates from the raw material that comprises 50% microcrystalline cellulose and 50% cornstarch and forms particle.Image 270 shows the SEM-image of unprocessed raw material.Image 271 show compress but also do not have the SEM-image of the particulate matter of classification.Use the thrust of 25kN in the experiment.Image 272 shows the SEM-image of the particulate matter of being accepted by the grading plant of embodiment of the present invention.Image 270 and 271 magnifying power are substantially similar, and image 272 and image 270 compare with 271 have 0.1 * magnifying power.Image 270 shows almost there is not particle.In image 271, notice is concentrated to the relatively undersized particle that produces in the compaction step.Particle in the material 271 of the compression that cylinder compacting machine and thin slice disintegrating machine (110 and 111 among Fig. 1 a and the 1b) produce is usually less than 500 μ m, and great majority are graded particle 272 that device (seeing Fig. 4) accepts greater than 500 μ m.This astonishing observed result was thought the inventor can to produce the new particle accepted in the classification stage of the method for embodiment of the present invention and/or particle can be further coalescent.

Fig. 2 h is presented at the particle size distribution figure of the material of describing in the image 271 and 272 of Fig. 2 g.According to the production verify data of the raw material that uses, the distribution of sizes of the particle of raw material (showing in the drawings) is that all particles of almost described material are all less than 106 μ m.When described material was compressed, as shown in the image 280, the ratio of the particle of acceptable size improved slightly, but the particle of great majority (about 73%) remains less than 106 μ m.After image 281 shows classifications, significantly increase greater than the particle ratio of 106 μ m.The part of accepting still comprises about 10% granule and/or minuteness particle less than 106 μ m.Although granule and/or the minuteness particle of relatively large ratio are arranged, material shows good flowability.The overall ratio of the particle of accepting from the material that compresses in classification step is about 10%.Therefore, about 90% material is graded device and eliminates.

Fig. 2 i shows the SEM-image on the surface of the particle that adopts the embodiment of the present invention preparation.In pelletization, used different thrusts.Shown material comprises 50% microcrystalline cellulose and 50% cornstarch.Image 290,291,292 is described respectively the particle of the thrust production of using 25kN, 40kN and 60kN.Notice that when thrust increased, surface porosity reduced.In the particle of image 290 and 291, can easily find many holes, and large compact area is arranged in the particle of image 292.Particle surface lacks the hole can make the properties of particulate matter worsen at least, and described character for example is the compressing tablet of flowability, material of material and/or the disintegration time of the tablet that obtains.Therefore, show that the optimal compression power of producing particle from this raw material may be lower than 60kN.Although SEM image 290 and 291 does not show significant difference in the surface texture of particle, but compare with the material that produces with the thrust of 40kN, the particulate matter that uses the thrust of 25kN to produce forms has higher tensile strength and the tablet of disintegration time faster.

Fig. 3 shows for removing minuteness particle and/or short grained exemplary hierarchical device from the particulate matter 303 of compacting machine generation.This device has chamber 300 (it comprises the hole for different purposes).Will be from the input material 301 of compacting machine and thin slice disintegrating machine through 302 chargings of one or more holes.Gravity makes material 305 flow to hole 304 downwards, and 304 outflow systems enter into container to the particulate matter 306 of acceptance through the hole.From identical hole 304, carrier gas (air) 307 flow in the system.Gas can also be from some other holes (its be positioned in can realize the carrier gas stream of expecting remove the position of minuteness particle and/or short grained effect) flow into the system.Carrier gas is to flow from the mobile different direction (adverse current) of the particle of accepting.The particle of accepting lands from grading plant by pipeline 304 through Action of Gravity Field.When particle moves in grading plant 300, minuteness particle and/or granule can with other particles coalesce, therefore particle is further increased.Carrier gas is flowed 309 via hole diameters 310 minuteness particle and/or granule 308 is taken away from grading plant.Can have for the particle of accepting and for minuteness particle and/or short grained a plurality of hole of eliminating.

Fig. 4 illustrates the example of improved grading plant.In the figure, with dashed lines draws assembly and the structure that is positioned at device inside.Device 400 comprises grading room and is installed in the cylinder 401 (or conical device, do not exemplify) of opening of the inside of this chamber, and this cylinder 401 rotatably is supported on the roller bearing 410.The adjustment of rotational speed of cylinder can be arrived for example at ROTAB ^TMGetable maximum in the device of the model 400EC/200 of (Warren, MI, USA).Can be with the outer cover perforation of cylinder or cone.Except should being constructed to make gas (air) and the minuteness particle that carries, described hole leaves the cylinder by them, to the quantity at possible hole or their edge and shape without limits.Described hole for example can be circular, oval-shaped maybe can be groove.In one embodiment, described hole is circular, and they cut with laser cutting technique.In one embodiment, the diameter of circular hole is 1.5mm.CD-ROM drive motor 402 is installed, so that with suitable speed (for example with 100 RPM) rotor.Provide helical structure 403 in cylinder interior, be used for along with the cylinder rotation is transported solid material from feed end 411 to outlet 404.Except helical structure, can provide various blades or other structure in cylinder interior, with the interaction of the movement of the material that realize to compress and itself and air-flow.Can adjust as required the angle of inclination of cylinder by the position that for example changes the whole grading plant 400 on its mounting structure 413,414.

The powder 405 that leaves hold down gag falls into the feed end 411 of cylinder by charging connector 412, and by helical structure 403 fortune to outlet conduit 404.Outlet 404 the carrier gas 406 of flowing through is moved with the direction opposite with the particle 407 of accepting.Can accept particle and move ahead along cylinder 401, and under Action of Gravity Field, drop in the product container (not showing) through exporting 404.May follow and to accept particle to unacceptable minuteness particle and/or the granule of pipeline 404 and usually can be transported back cylinder 401 from pipeline 404 by air-flow 406.In apparatus of the present invention, outlet 404 pipelines that refer to downwards, its length is 70mm, diameter is 40mm.Minuteness particle and/or the granule 408 of eliminating part flow to feed conveying device (seeing 102 among Fig. 1) with carrier gas stream by connector 409, are used for processing again.Particle can increase dimensionally in grading plant 400 (or 300 among Fig. 3).Described coalescent may being caused by for example frictional electricity and electrostatic force.

The character of the part of accepting for example can be changed the rotating speed of cylinder, the angle of inclination of cylinder, the pitch of helical structure and size, quantity and the position in the hole in the cylinder and the flow velocity of shape and change carrier gas affects.

Fig. 5 a and 5b show two kinds of multi-form cylinder-shaped devices being arranged in grading plant inside (see Fig. 4 400).Cylinder 500 has hole 501, and it is positioned at the whole outer cover of cylinder in Fig. 5 a, and only the end at cylinder is porose in Fig. 5 b.The cylinder of the input material 502 that will contain particle and minuteness particle from an endfeed of cylinder to rotation.Rotatablely moving of cylinder 500 and cylinder interior helical structure (seeing 403 among Fig. 4) 503 promotes the input materials and moves towards the other end of cylinder.When material just moved in cylinder, carrier gas stream 504 was isolated acceptable particle from the minuteness particle eliminated and/or granule 505, and superseded minuteness particle and/or granule 505 501 are shifted out cylinder by the carrier gas circulation through the hole.By the helical structure that is positioned at cylinder interior the particle 506 of accepting is released cylinder at last.

In the embodiment illustrated, whirligig is the cylinder of diameter 190mm and length 516mm, and it comprises the hole, and each hole has the diameter of 1.5mm, and the mutual average headway in hole is 6mm.The air-flow that enters grading plant by hole 404 (Fig. 4) leaves grading room for processing by the hole (409 among Fig. 4) of diameter 50mm more again.In cylinder interior the spiral guiding structure is arranged, the every rotation of this structure 80mm that once advances to the hole of accepting material 506.The height of guide structure is 25 millimeters.Fig. 5 c shows the figure of exemplary corrosion resistant plate with holes, can construct suitable cylinder with this steel plate.The thickness of steel is about 0.8mm.Above-mentioned ROTAB ^TMDevice has carried out following modification: cylinder is changed into the cylinder that the steel plate by Fig. 5 c is combined into, and grading room has been changed into have be similar to Fig. 4 400 shown in the grading room of shape of grading room.

Although the device shown in Fig. 5 a and the 5b be opening with columnar, and the motion that relates to is to rotatablely move, and can also and utilize the conveying device of other kinds of athletic to transport material in the classification air-flow with other shapes.

Can randomly device be revised to improve its continuous disposal ability.A kind of described modification is disclosed among Fig. 6, wherein with figure a kind of double filter device has been described.In cyclone separator 602 (also seeing 106 among Fig. 1 a or the 1b), most of minuteness particles and/or granule are separated from carrier gas (for example air), but some minuteness particles and/or granule can be sucked out cyclone separator along with carrier gas.Before system is left in carrier gas, may need with above-mentioned particulate filter out.Filter 607a, 607b collect minuteness particle and/or granule until filter is cleared up.Filter 607a, a 607b can play a role, and another is just being cleared up for example by vibrating it.Valve 605,612 can be used for the filter of steering current by just playing a role, and for the filter that will wait to be cleared up and air-flow isolation.When opening respectively valve 608a, 608b, from the powder that obtains of cleaning filter fall filter below and further to pipeline 609a, 609b.At the other end of pipeline, lower valve 610a, 610b can be arranged, after top valve 608a, 608b closes, open valve 610a, 610b.Opening lower valve falls back in the circulation for processing powder again.When equipment in when running, this configuration is so that one of cleaning filter becomes possibility, and cleaning operation can not cause the nebulizer gas pressure vibrations of not expecting in equipment.

Described equipment can also randomly assemble the sensor of for example measuring in real time the size of the particle of accepting.Described configuration is presented among Fig. 7.The particle of accepting leaves grading plant 700 by pipeline 701.Light emitting devices 702 and light sensor 703 are installed in the size of accepting particle of passing through with observation in the pipeline.According to the information that sensor produces, the control logic of system can be adjusted the operating parameters of equipment.A kind of described adjustable parameter can be the size that 704 particles that produce are sieved in for example thin slice fragmentation.The airflow rate that another kind of described adjustable parameter can be system.

Fig. 8 marginal data is used for powder is granulated separately, the exemplary optional configuration that then particle is mixed.Compare with in a process, granulating, in a plurality of pelletizations, the formulation components granulation can be affected the character (for example disintegration time) of finished product (for example tablet).

Granulating system 801,802 is produced particle from different material (or from identical material, but with the different grain made parameters size of the particle of thrust or acceptance for example) separately.Each system has the device 811,812 that oneself adjusts grain made parameter.Make particle from the acceptance of each granulating system by conveying device 803,804 to the particle mixing arrangement, this device has the device 806,807 for the amount of every kind of particle of control final mixture.Mixing arrangement can also have particle mixing arrangement 808, before particle is mixed in order to flow to finished product container 810 or flow directly to tablet press machine (not show) at particulate matter.Conveying device 803, the 804th among Fig. 8, towards the pipeline of mixing arrangement, but conveying device can also guide particle to the intermediate storage container, material can be transported to mixing arrangement from this container.

Fig. 9 marginal data is used for measuring the simple mechanism of powder or particulate matter flowability.Measure in various degree flowability with the device of different size.Mobile degree can be enough, good, very good or good.

The device that is used for measuring enough flowabilities comprises the cone 900 of level and smooth frosting, and it has the circular hole 903 of 12 millimeters of the cone angles 902 of 45 millimeters height 901 and about 59 degree and diameters.The length of pipeline 904 is 23mm.In the fluidity testing method, when circular hole 903 remains closed, cone is filled powder or particulate matter.Open circular hole, rap cone and flow beginning, and observe and only rely on gravity powder flowing by circular hole.Guarantee that at test period cone does not have other vibration or the motion of other type.If cone is basic empty, then this material passes through fluidity testing." substantially " refers to that at least 85%, 90% or 95% powder leaves cone herein.

The device that is used for adopting method of testing recited above to measure good fluidity comprises the cone 900 of level and smooth glass surface, and it has the circular hole 903 of 7 millimeters of the cone diameter 905 of 50 millimeters height 901 and 70mm and diameters.The length of pipeline 904 is 70mm.

Be used for measuring the cone 900 that the unusual device of good fluidity comprises level and smooth frosting, it has the circular hole 903 of 4 millimeters of the cone diameter 905 of 35 millimeters height 901 and 48mm and diameters.The length of pipeline 904 is 50mm.

Device that be used for to measure excellent fluidity comprises the cone 900 of level and smooth frosting, and it has the circular hole 903 of 3 millimeters of the cone diameter 905 of 40 millimeters height 901 and 55mm and diameters.The length of pipeline 904 is 60mm.

Use above-mentioned or other the embodiment of the present invention, can produce the particle of the general aspects (for example good fluidity, good compressibility, good compressing tablet, the fast disintegration time of tablet and high medicine carrying capacity) with one or more expectations.We observe these character and are applicable to many APIs and excipient.Therefore, for many APIs, can avoid parts that in the pharmaceutical preparation method for designing of prior art some may be time-consuming and expensive.Shown in embodiment relative cost efficient is still arranged for building and using.The configuration of for example, building the particle per hour can produce several kilograms or tens of kilograms is possible.Compare with the wet granulation method of for example prior art, the method is still relatively simple and be easy to control.In the embodiment illustrated, having seldom, number may need controlled parameter.

Unless additionally explanation, the percentage of giving in the literary composition (%) value is with regard to weight.

Unless additionally explanation, mean value is geometrical mean.

The following examples are described the character of using the more available typical particles of embodiment of the present invention and tablet.

Embodiment

Character and Qi Ke compressing tablet for the particulate matter of observing the various embodiments of the present invention have carried out a series of tests.In all tests, use the in this article method and apparatus of (for example Fig. 1 b and Fig. 4) description.The gas flow rate of adjustment equipment produces the particulate matter with good, very good or good flowability so that the grading of air-flow causes.Make the induced-draught fan (BUSCH of system ^TMMink MM 1202 AV) operate to produce airflow rate in the test in the default rate of about 1860 RPM.For some materials, speed is changed from default value, to obtain the particulate matter of desired qualities.The thrust of adjustment cylinder compacting machine has best compressing tablet character with production particle.With the power used with thousand newton's records, shown in the cylinder compacting machine (HOSOKAWA BepexPharmapaktor L200/50P) that uses in the test.The diameter of cylinder of compacting machine is 200mm, and the working width of cylinder is 50mm.The thickness of the ribbon that compacting machine produces is about 4mm.The rotating speed of cylinder is 10-12 RPM normally.By the definite thrust of rotating speed to obtain expecting of cylinder compacting machine adjustment.The acquiescence aperture size of the broken sieve of thin slice is 1.00mm.In some experiments, leave the mesh size of the broken sieve of thin slice under order default value.

Unless make different explanations, will be at the grading plant of the whirligig shown in Fig. 4 of about 100 RPM running as testing equipment.The default size in the hole on the cylinder of whirligig is 1.5mm.

In the test of all compressing tablets, before compressing tablet, 0.25% dolomol is added in the particulate matter, as lubricant.

The cornstarch of usefulness estimates to have the granularity of 5-30 micron in test.

Use MECMESIN ^TM(Mecmesin Limited, West Sussex, UK), the measurement mechanism of model BFG200N is measured the tensile strength of tablet.

Be set with to measure the size distribution of particulate matter with sieve.In measurement, use at energy and be set to 6 electromagnetic sieve vibrator (manufacturer: C.I.S.A Cedaceria Industrial, S.L, model: RP 08) with the suit vibration of four sieves 5 minutes.The opening size of used sieve is 850 μ m, 500 μ m, 250 μ m and 106 μ m.

Compressing tablet embodiment 1-90% acebutolol hydrochloride

The powdered rubber that 5.0kg is contained 90% acebutolol hydrochloride powder (27 microns of particle mean sizes) and 10% starch mixes.The thrust of using 40kN is compacted into material the particle of the standard deviation of the mean size that has 877 microns after the classification and 1.421.The loose bulk density of the material that obtains is 0.68g/ml, and this material has good flowability.Make the circular tablet of diameter 10mm and weight 500mg with the 6-8kN compression force.The average tensile strength of tablet is 80N (N=10).The disintegration time of the tablet of observing in the water near body temperature is about 6.5 minutes.

Compressing tablet embodiment 2-20% fluoxetine hydrochloride

To contain 20% (2.24kg) fluoxetine hydrochloride (manufacturer: SIFAVITOR SpA, Casaletto Lodigiano, Italy, lot number 2700/01/06), 64% (7.168kg) microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3682) and the powdered rubber of 16% (1.792kg) cornstarch (CERESTAR Mat.no.03401, batch 01015757) mix.The thrust of using 35kN is compacted into described material the particle of the standard deviation of the mean size that has 461 microns after the classification and 2.358.The mesh size of the broken sieve of thin slice is set as 1.25mm.The loose bulk density of the material that obtains is 0.595g/ml, and described material has good flowability.Push up the circular tablet (N=10, standard deviation=1.89%) that the maximum compression force of splitting is made diameter 6mm and average weight 112mg with not producing.The average tensile strength of tablet is 44N (N=10, standard deviation=11.17%).The disintegration time of observing tablet in the water near body temperature is about 10 seconds.

Compressing tablet embodiment 3-60% paracetamol

About 4.0kg is contained 60% paracetamol attritive powder (manufacturer: Mallinckrodt Inc.-Ralcigh (USA)-batch 7845906C563,59% particle is less than 20 microns, 96% particle is less than 75 microns), 20% microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3689,50% particle is less than 71 microns) and the powdered rubber of 20% cornstarch (CERESTAR Mat.no.03401, batch 01015757) mix.The thrust of using 30kN is compacted into described material the particle of the standard deviation of the mean size that has 645 microns after the classification and 1.464.The mesh size of the broken sieve of thin slice is set as 1.00mm.The loose bulk density of the material that obtains is 0.586g/ml, and this material has good flowability.Push up the circular convex tablet (N=10, standard deviation 0.6%) that the maximum compression force of splitting is made diameter 10mm and average weight 454mg with not producing.This is extraordinary result, because think that so far the tablet (if not impossible words) that adopts the particle of dry granulation method preparation to produce the high carrying capacity of paracetamol by compacting is difficult.The average tensile strength of tablet is 49N (N=10, standard deviation=12.73%).The disintegration time of observing tablet in the water near body temperature is less than 1 minute.

Compressing tablet embodiment 4-90% sodium vedproate

Chemische Fabrik Berg), (PHARMACOAT 606 for 5% Hydroxypropyl methylcellulose 5.56kg is contained 90% sodium vedproate (manufacturer:, batches 5115055) and the powdered rubber of 5% cornstarch (CERESTAR Mat. number 03401, batch 01015757) mix.The thrust of using 35kN is pressed into described material the particle of the standard deviation of mean size with 550 microns and 1.686.The mesh size of the broken sieve of thin slice is set as 1.25mm.The loose bulk density of the material that obtains is 0.532g/ml, and this material has good flowability.Push up the circular convex tablet (N=10, standard deviation=1.29%) that the maximum compression force of splitting is made diameter 12mm and average weight 560mg with not producing.The average tensile strength of tablet is 84N (N=10, standard deviation=11.80%).Because as the sustained release property that the Hydroxypropyl methylcellulose of excipient is introduced, the disintegration time of observing tablet in the water near body temperature is 40 minutes.

Compressing tablet embodiment 5-50% Ketoprofen

About 8.0kg is contained 50% Ketoprofen (manufacturer: Ketoprofen S.I.M.S.Societ à italiana medicinali Scandicci, batches 121.087,79% particle is less than 60 microns) and the powdered rubber of 50% cornstarch (CERESTAR Mat. number 03401, batch SB4944) mix.The thrust of using 40kN is pressed into material the particle of the standard deviation of mean size with 900 microns and 1.418.The mesh size of the broken sieve of thin slice is set as 1.00mm.The loose bulk density of the material that obtains is 0.625g/ml, and this material has good flowability.Push up the circular convex tablet (N=10, standard deviation=1.94%) that the maximum compression force of splitting is made diameter 6mm and average weight 94mg with not producing.The average tensile strength of tablet is 39N (N=10, standard deviation=14.56%).The disintegration time of observing tablet in the water near body temperature is about 10 seconds.

Compressing tablet embodiment 6-80% Metformin

Use the thrust of 35kN that about 4.0kg is contained 100% Metformin (supplier: SIMS trading (Firenze, Italy), powdered rubber batches 21.039) compresses to produce the particle of the standard deviation of mean size with 668 microns and 1.554.The mesh size of the broken sieve of thin slice is set as 1.00mm.The loose bulk density of the material that obtains is 0.694g/ml, and this material has good flowability.Individually; to comprise 70% microcrystalline cellulose (EMCOCEL CAS 9004-34-6; batch 5S3689) and the excipient granule of 30% cornstarch (CERESTAR Mat. number 03401, batch 01015757) mix, and use same thrust to granulate.Then, 80% melbine particle is mixed with 20% excipient granule and be pressed into tablet.Push up the circular convex tablet that the maximum compression force of splitting is made diameter 12mm and comprised the 500mg melbine with not producing.The average tensile strength of tablet is 59N (N=3).Do not measure the disintegration time of tablet.

Except compressing tablet embodiment, the Hausner ratio by measurement of species and observe compressibility and the flowability that the flowability of material is tested the particulate matter of embodiment of the present invention.The method that will can be used for calculating the Hausner ratio and observing flow of matter is described in previous section of the present disclosure.

Mobile embodiment 1-100% paracetamol

The broken sieve screen apertures size of thin slice of using the thrust of 12kN and 1.00mm contains 100% paracetamol with 4.0kg, and (manufacturer: powdered rubber Mallinckrodt Inc.-Raleigh (USA)-batch 6088906C107) is pressed into the particle of the standard deviation of the average-size that has 708 microns after the classification and 1.349.0.58% particle of described material has the diameter less than 106 microns.The bulk density of the material that obtains is 0.610g/ml, and the real bulk density of pier is 0.758g/ml.The Hausner ratio of material is calculated as 1.24.Although the relative high compressibility of Hausner ratio indication is arranged, the flowability of also observing material is good.

Mobile embodiment 2-90% Metformin

To contain 90% (4.0kg) melbine (METFORMIN HYDROCHLORIDEUSP, batch N.17003742, USV LIMITED, B.S.D.Marg.Govandi, Mumbay400 088, India), the powdered rubber of 8% (356g) microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3682) and 2% (88g) cornstarch (CERESTAR Mat. number 03401, batch 01015757) mixes.Adopt the induced-draught fan speed of the broken sieve screen apertures size of thin slice of thrust, 1.00mm of 30kN and 2100 RPM to come to have after the production classification 477 microns average-size and the particle of 2.030 standard deviation.11.0% particle of this material has the diameter less than 106 microns.The loose bulk density of the material that obtains is 0.581g/ml, and the real bulk density of pier is 0.714g/ml.The Hausner ratio of described material is determined as 1.23.Although the relatively high compressibility of Hausner ratio indication is arranged, the flowability of also observing described material is good.When testing with melbine, the inventor also obtains unexpected observed result, although when serious coalescent (the forming large, hard agglomerated thing) of 100% melbine attritive powder performance when room temperature and ambient humidity are stored, in fact the 100% melbine particle that uses the described powder that method of the present invention prepares does not show above-mentioned coalescent at lay up period.

Mobile embodiment 3-excipient

The powdered rubber that will about 3.0kg comprises 70% microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3689) and 30% cornstarch (CERESTAR Mat. number 03401, batch 01015757) mixes.Adopt the broken sieve screen apertures size of thin slice of the thrust of 16kN and 1.00mm to come to have after the production classification 318 microns average-size and the particle of 2.159 standard deviation.The particle of 19.6% material has the diameter less than 106 microns.The loose bulk density of the material that obtains is 0.379g/ml, and the real bulk density of pier is 0.510g/ml.The Hausner ratio measure of material is 1.35.Although the relatively high compressibility of Hausner ratio indication, it is good observing flowability.

Mobile embodiment 4-20% Ketoprofen

Will about 4.0kg comprising 20% Ketoprofen (S.I.M.S.Societ à italiana medicinaliScandicci, batch 121.087) and the powdered rubber of 80% microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3689) mixes.Adopt the thrust of 24kN and the broken sieve screen apertures size of thin slice of 0.71mm to produce particle.When with the induced-draught fan Speed Setting of system during at 1980 RPM, after the classification, the average-size of the particle of acceptance is 304 microns, and standard deviation is 2.275.23.0% material has the granularity less than 106 microns.The loose bulk density of material is 0.510g/ml, and the real bulk density of pier is 0.676g/ml.The Hausner ratio measure of material is 1.325.The flowability of observing material is enough.When with the induced-draught fan Speed Setting of system at 2400 RPM, after the classification, the average-size of the particle of acceptance is 357 microns, and standard deviation is 2.121.13.7% material has the particle size less than 106 microns.The loose bulk density of this material is 0.521g/ml, and the real bulk density of pier is 0.714g/ml.The Hausner ratio measure of material is 1.371.The flowability of observing material is good.Present embodiment shows the gas flow rate by the change system, can obtain having the particulate matter of different flowing properties.Opposite with instruction in the prior art (for example the U.S. patent 6,752,939), present embodiment shows that also the Hausner ratio must not indicate the flowability of particulate matter.For example, compare with the compressibility of particulate matter, the size distribution of particulate matter may have larger impact by flow.Therefore, good compressibility and flowability can coexist as same particulate matter.

Capacity embodiment

The embodiment of describing in the disclosure can be produced very a large amount of particulate matters.In the volume test of an embodiment that comprises Fig. 4 grading plant, with 5,98kg paracetamol (7845 paracetamol attritive powder-Mallinckrodt Inc.-Raleigh (USA)-batch 7845906C563), 10,69kg microcrystalline cellulose (CAS 9004-34-6-JRS PHARMA LP-Patterson (USA)-batch 5S3689), 37, (CERESTAR Mat. number 03401 for the 10kg cornstarch, batch 01015757), 12,19kg lactose (lactose monohydrate-DMV InternationalPharmatose 80M DP5500 batch 10,209,285 906535704), 34,04kg cellulose (Germany-batch of G13060620 of " Technocel "-CFF GmbH-Gehren) mixes, and uses the thrust of about 40kN and the induced-draught fan speed of 2160 RPM to granulate.Make equipment operation 2 hours 38 minutes, and produced the particle that 94,66kg has good fluidity character at least.

Classification embodiment 1

The powdered rubber that will about 5.0kg comprises 50% microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3689) and 50% cornstarch (CERESTAR Mat. number 03401, batch 01015757) mixes and granulates.In pelletization, stop the again processing of the material that is eliminated.Described in order to realize, the material that will process manually is fed to intermediate receptacle (107 among Fig. 1 b), by opening valve (109 among Fig. 1 b) described material is transported to compacting machine (110 Fig. 1 b) from this container before beginning processing.Then, begin to process, and the 5.0kg material is granulated and classification.In processing procedure, make valve (109 among Fig. 1 b) keep closing to stop the again processing of the part that is eliminated.Come to have after the production classification particle of 523 microns average-sizes (standard deviation 1.70) with the broken sieve screen apertures size of the thin slice of the thrust of 40kN and 1.00mm.This test run produces the particle of accepting of 1630g (32.6%).The SEM image of accepting the surface of particle is presented in the image 291 of Fig. 2 i.Remaining material is graded device and eliminates.Particle/particle of 4.0% of accepting material has the diameter less than 106 microns.The loose bulk density of the material that obtains is 0.56g/ml, and the real bulk density of pier is 0.641g/ml.The Hausner ratio measure of this material is 1.15.The flowability of observing the receiving portion is good.On the other hand, it is inadequate observing the flowability of eliminating part.

Superseded part comprise 16.4% greater than 250 microns particle, and the part of accepting comprise 92% greater than 250 microns particle.

Compressing tablet for the receiving portion of observing particulate matter is added to 0.5% dolomol in the described material, and the tablet of production average weight 588mg.The average tensile strength of tablet (N=6) is measured as 23.56N, and standard deviation is 1.308.The disintegration time of observing tablet is about 12 seconds.

Classification embodiment 2

The powdered rubber that will about 4.0kg comprises 50% microcrystalline cellulose (EMCOCEL CAS 9004-34-6, batch 5S3689) and 50% cornstarch (CERESTAR Mat. number 03401, batch 01015757) mixes and granulates.Be different from top embodiment, will be used for according to the grading plant of the embodiment of disclosure Fig. 1 a and 3 classification step of this process.In pelletization, stop the again processing of the part that is eliminated.Described in order to realize, pending material manually is fed to intermediate receptacle (107 among Fig. 1 a), before beginning processing, by opening valve (109 among Fig. 1 a) described material is transported to compacting machine (110 Fig. 1 a) from described container.Then, begin to process, and the 4.0kg material is granulated and classification.In processing procedure, make valve (109 among Fig. 1 a) keep closing to stop the again processing of superseded part.Come to have after the production classification particle of 437 microns average-sizes (standard deviation 2.42) with the broken sieve screen apertures size of the thin slice of the thrust of 16kN and 1.00mm.This test run produces the particle of accepting of 670g (16.75%).Remaining material is graded device and eliminates.Accept 20.9% particle of material/particle and have the diameter less than 106 microns.The loose bulk density of the material that obtains is 0.455g/ml, and the real bulk density of pier is 0.568g/ml.The Hausner ratio measure of this material is 1.248.Except such as the indicated height compressibility of accepting material of Hausner ratio, it is good observing flowability.On the other hand, it is inadequate observing the flowability of eliminating part.

Superseded part comprise 7.1% greater than 250 microns particle, and the part of accepting comprise 68.4% greater than 250 microns particle

For the compressing tablet of the receiving portion of observing particulate matter, the dolomol with 0.5% is added in the described material, and the tablet of production average weight 584mg.The average tensile strength of tablet is measured as 63.34N, and standard deviation is 6.78 (N=6).Tensile strength that it should be noted that tablet is significantly higher than among the classification embodiment 1.The disintegration time of observing tablet is about 12 seconds.

For a person skilled in the art, the exemplary of front is illustrated in this application the example of statement, designs accordingly that different to utilize method, system, particle and the tablet of the inventive concept set forth that proposes among the application in apparent mode be possible.

Claims

1. from the method for powder production particle, it is characterized in that: will hang down thrust and be applied to powder comprises the mixture of minuteness particle and particle with production the material of compression, and by in air-flow, carrying away minuteness particle minuteness particle is separated from particle, the material of wherein said compression flows in described air-flow, and wherein the direction of air current flow has the component with the opposite direction of the flow of matter that compresses, and wherein by the equipment that comprises grading plant minuteness particle is separated from particle, wherein grading plant comprises whirligig, and material axle along whirligig in described air-flow of compression is moved.

2. according to claim 1 method, wherein thrust be enough low so that 75% or the powder of following weight be packed together to the acceptable particle that has greater than the granularity of 150 μ m, and remainder remains minuteness particle and/or granule.

3. according to claim 1 or the method for claim 2, wherein by comprising that the method for using for generation of the cylinder compacting machine of the ribbon of powder compaction puts on powder with thrust, the broken particle that produces of described ribbon.

4. according to claim 1 or the method for claim 2, wherein thrust is Hosakawa ^TM60kN in the Bepex Pharmapaktor L200/50P cylinder compacting machine or less thrust.

5. according to claim 1 or the method for claim 2, wherein thrust is Hosakawa ^TM16kN in the Bepex Pharmapaktor L200/50P cylinder compacting machine or larger thrust.

6. according to claim 1 or the method for claim 2, wherein the direction of air current flow is substantially opposite with the direction of the flow of matter of compression.

7. according to claim 1 or the method for claim 2, it is characterized in that making the material of described compression mobile in said flow by mechanical means.

8. according to claim 1 or the method for claim 2, wherein said whirligig is cylinder or cone.

9. the material that wherein compresses according to claim 1 or the method for claim 2, is guided by helical structure along the movement of the axle of whirligig.

10. according to claim 1 or the method for claim 2, wherein said grading plant contains porose, and minuteness particle and/or granule are carried away by this hole.

11. for the production of the method according to claim 10 of the particle of average expectation size x, its mesopore has the minimum dimension of 1.0x.

12. the residence time of material in grading plant that wherein compresses according to claim 1 or the method for claim 2, was at least 2 seconds.

13. according to claim 1 or the method for claim 2, be characterised in that described powder comprises excipient and/or the active pharmaceutical ingredient that can be used for pharmaceutical preparation.

14. method according to claim 13, wherein said powder comprises the active pharmaceutical ingredient of the amount of at least 60% weight.

15. according to claim 1 or the method for claim 2, wherein minuteness particle and/or the granule recirculation that carries out is used for compressing.

16. according to claim 1 or the method for claim 2, the method also comprises the step of collecting granules.

17. the particulate matter of dry granulation, it comprises the available particle of method according to claim 16.

18. the particulate matter of dry granulation according to claim 17, be characterised in that it contains the particle of the average-size with 100 μ m to 3mm, this particle is comprised of following part: (a) core of compacting, and it comprises the minuteness particle of the material that is associated by Van der Waals force; (b) coated layer, this coated layer comprises minuteness particle and/or the granule of described material, and they are associated with the core of compacting by electrostatic force.

19. the particulate matter of dry granulation according to claim 17, be characterised in that it contains the particle of the average-size with 100 μ m to 3mm, this particle is comprised of following part: (a) core of compacting, and it comprises the minuteness particle of the material that is associated by Van der Waals force; (b) the coated layer of porous, it comprises minuteness particle and/or the granule of described material.

20. according to claim 18 or the dried particulate matter of claim 19, the particle mean size that is characterised in that the particle of material is 1-100 μ m, the average-size of the core of compacting is 50-3000 μ m, and the ratio of the average-size of the core of the minuteness particle of coated layer material and/or short grained particle mean size and compacting is at least 1: 10.

21. according to claim 18 or the dried particulate matter of claim 19, wherein said particulate matter comprises the active pharmaceutical ingredient that is selected from Acebutolol, Fluoxetine hydrochloride, paracetamol, sodium vedproate, Ketoprofen and Metformin hydrochloride.

22. according to claim 17 or the particulate matter of the dry granulation of claim 18, but is characterised in that described material is compressing tablet, and has good flowability, and this material comprises at least a following drug ingedient of at least 10% weight:

-Acebutolol,

-Fluoxetine hydrochloride,

-paracetamol,

-sodium vedproate,

-Ketoprofen and

-Metformin hydrochloride.

23. prepare the method for tablet, the method comprise compacting optional with one or more other mixed with excipients according to claim 17 or the particulate matter of the dry granulation of claim 18.

24. the available tablet of method by claim 23.

25. tablet according to claim 24, it comprises at least a following active pharmaceutical ingredient of at least 10% weight:

-Acebutolol,

-Fluoxetine hydrochloride,

-paracetamol,

-sodium vedproate,

-Ketoprofen and

-Metformin hydrochloride.

26. tablet, this tablet by compacting according to claim 17 or the particulate matter of the dry granulation of claim 18 make, described particulate matter comprises 60% or the active pharmaceutical ingredient that is selected from paracetamol, Metformin hydrochloride, Acebutolol and sodium vedproate of more multiple amount.

27. be used for the equipment of dry granulation, be characterised in that this equipment comprises the hold down gag that can produce low thrust and the grading plant that is suitable for by carry away minuteness particle in air-flow minuteness particle being separated from the material that compresses, the material of wherein said compression flows in air-flow, and wherein the direction of air current flow has the component with the opposite direction of the flow of matter that compresses, and wherein grading plant comprises whirligig, and material axle along whirligig in described air-flow of compression is moved.

28. equipment according to claim 27, wherein thrust applies for generation of the device of the cylinder compacting machine of the ribbon of powder compaction by comprising use, the broken particle that produces of described ribbon.

29. according to claim 27 or the equipment of claim 28, the material by mechanical means mobile described compression in described air-flow wherein.

30. according to claim 27 or the equipment of claim 28, wherein the direction of air current flow is substantially opposite with the direction of the flow of matter of compression.

31. according to claim 27 or the equipment of claim 28, be characterised in that described grading plant comprises at least a structure be used to guiding the material of described compression in the described grading plant.

32. according to claim 27 or the equipment of claim 28, wherein said whirligig is cylinder or cone.

33. equipment according to claim 32, the material that wherein compresses is advanced by helical structure along the movement of the axle of whirligig.

34. according to claim 27 or the equipment of claim 28, wherein grading plant contains porosely, and minuteness particle and/or granule are carried away by this hole.

35. for the production of the equipment according to claim 34 of the particle of average expectation size x, its mesopore has the minimum dimension of 1.0x.

36. according to claim 27 or the equipment of claim 28, wherein grading plant does not need to make the material of compression by any sieve.

37. be used for the equipment of dry granulation, be characterised in that this equipment comprises the hold down gag that can produce low thrust and the grading plant that is suitable for by carry away minuteness particle in air-flow minuteness particle being separated from the material that compresses, the material of wherein said compression flows in air-flow, wherein the direction of air current flow has the component with the opposite direction of the flow of matter that compresses, and wherein grading plant does not need to make the material of compression by any sieve.

38. be suitable for the grading plant that minuteness particle separated by in air-flow, carrying away minuteness particle and/or granule from the material that compresses, this device comprises whirligig, make material axial flow along this whirligig in said flow of compression moving, and this whirligig contains porose, minuteness particle and/or granule are carried away through this hole, and wherein the direction of air current flow has component with the opposite direction of the flow of matter that compresses.

39. grading plant according to claim 38, wherein said whirligig are cylinder or cone.

40. according to claim 38 or the device of claim 39, wherein the direction of air current flow is substantially opposite with the direction of the flow of matter of compression.

41. the material that wherein compresses according to claim 38 or the device of claim 39, is guided by helical structure along the movement of the axle of whirligig.