WO2009101258A1

WO2009101258A1 - Novel pharmaceutical formulation

Info

Publication number: WO2009101258A1
Application number: PCT/FI2009/050111
Authority: WO
Inventors: Erkki Heilakka; Giovanni Politi
Original assignee: Atacama Labs Oy
Priority date: 2008-02-15
Filing date: 2009-02-13
Publication date: 2009-08-20
Also published as: FI20080348A0

Abstract

The invention provides a method for producing granules from a powder comprising at least 60 % w/w of ibuprofen sodium dihydrate, characterized in that compaction force is applied to the powder to produce a compacted mass comprising a mixture of fine particles and granules and separating and removing fine particles and/or small granules from the granules by entraining the fine particles and/or small granules in a gas stream. A dry-granulated mass and a tablet comprising ibuprofen sodium dehydrate and a process for preparing a tablet are provided.

Description

NOVEL PHARMACEUTICAL FORMULATION

TECHNICAL FIELD OF INVENTION

The invention relates to granules and tablets comprising ibuprofen sodium and method and apparatus for their production.

BACKGROUND OF THE INVENTION

Ibuprofen is one of the most frequently used non-steroidal anti-inflammatory drug. One of its characteristics is a low melting point which sets some limitations to the formulation of ibuprofen into dosage forms, such as tablets. In spite of the formulation challenges, ibuprofen is available in multiple different dosage forms, including tablets.

Ibuprofen sodium, e.g. ibuprofen sodium dihydrate, is a salt of ibuprofen that has some advantages over other forms of ibuprofen. For example, it is freely soluble to water. On the other hand, the formulation of ibuprofen sodium, e.g. as a dihydrate, e.g. into tablets has proven to be a very challenging task, especially if a high drug load and/or quick disintegration and/or dissolution time is desired from the tablet.

Generally, a solid bulk of granulate mass, which is necessary for manufacturing tablets, can be manufactured using two main processes, wet granulation or dry granulation. Tablets may also be manufactured using direct compression. Direct compression relates to the tableting process itself rather than preparation of the starting material.

In wet granulation, components are typically mixed and granulated using a wet binder. The wet granulates are then sieved, dried and optionally ground prior to compressing into tablets. Wet granulation is used extensively in the pharmaceutical industry although it has proven to be a difficult method, mainly because the liquids needed in the granule and tablet manufacturing process often have an adverse effect on the characteristics of the active pharmaceutical ingredients (APIs) and/or on the end product such as a tablet.

Dry granulation is usually described as a method of controlled crushing of precompacted powders densified by either slugging or passing the material between two counter-rotating rolls. More specifically, powdered components that may contain very fine particles are typically mixed prior to being compacted to yield hard slugs which are then ground and sieved before the addition of other ingredients and final compression to form tablets. Because substantially no liquids are used in the dry granulation process, the issues related to wet granulation are avoided. Although dry granulation would in many cases appear to be the best way to produce products such as tablets containing APIs, it has been relatively little used because of the challenges in producing the desired kind of granules as well as managing the granulated material in the manufacturing process. Known dry granulation methods, as well as the known issues related to them are well described in scientific articles, such as the review article "Roll compaction / dry granulation: pharmaceutical applications" written by Peter Kleinebudde and published in European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) at pages 317-326.

Direct compression is generally considered to be the simplest and the most economical process for producing tablets. However, it may only be applied to materials that don't need to be granulated before tableting. Direct compression requires only two principal steps; i.e., the mixing of all the ingredients and the compression of this mixture. However, direct compression is applicable to only a relatively small number of substances as the ingredients of the tablets often need to be processed by some granulation technique to make them compressible and/or for improving their homogeneity and flow-ability.

A component of a tablet is usually described as being either an excipient or an active ingredient. Active ingredients are normally those that trigger a pharmaceutical, chemical or nutritive effect and they are present in the tablet only in the amount necessary to provide the desired effect. Excipients are inert ingredients that are included to facilitate the preparation of the dosage forms or to adapt the release characteristics of the active ingredients, or for other purposes ancillary to those of the active ingredients.

Excipients can be characterized according to their function in the formulation as, for instance, lubricants, glidants, fillers (or diluents), disintegrants, binders, flavors, sweeteners and dyes.

Lubricants are intended to improve the ejection of the compressed tablet from the die of the tablet-making equipment and to prevent sticking in the punches.

Glidants are added to improve the powder flow. They are typically used to help the component mixture to fill the die evenly and uniformly prior to compression.

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

Disintegrants may be added to formulations in order to help the tablets disintegrate when they are placed in a liquid environment and so release the active ingredient. The disintegration properties usually are based upon the ability of the disintegrant to swell in the presence of a liquid, such as water or gastric juice. This swelling disrupts the continuity of the tablet structure and thus allows the different components to enter into solution or into suspension

Binders are used to hold together the structure of the tablets. They have the ability to bind together the other ingredients after sufficient compression forces have been applied and they contribute to the integrity of the tablets.

Finding the proper excipients for particular APIs and determining the proper manufacturing process for the combination of excipients and APIs can be a time- consuming job that may lengthen the design process of a pharmaceutical product, such as a tablet significantly, even by years. Both the dry and wet granulation methods of the prior art may produce solid bridges between particles within granules that may be undesirable for example in that they lead to unsatisfactory subsequent tablet characteristics. The solid bridges may be caused by partial melting, hardening binders or crystallization of dissolved substances. Partial melting may for example occur when high compaction force is used in dry granulation methods. When the pressure in the compaction process is released, crystallization of particles may take place and bind the particles together. Because of the very low melting point of ibuprofen sodium dihydrate, dry granulation has not been regarded as a usable formulation process for this particular API.

Electrostatic forces may also be important m causing powder cohesion and the initial formation of agglomerates, e.g. during mixing. In general they do not contribute significantly to the final strength of the granule Van der Waals forces, however, may be about four orders of magnitude greater than electrostatic forces and can contribute significantly to the strength of granules, e.g. those produced by dry granulation The magnitude of these forces increases as the distance between particle surfaces decreases

In addition to finding a practical manufacturing process for a pharmaceutical product, validation of the manufacturing process is essential. Validation means that the process must be able to reliably produce a consistently acceptable and predictable outcome each time the process is used. Wet granulation methods are quite challenging to manage in this respect. The wet granulation process is often quite vulnerable to small changes in manufacturing conditions.

It is also well known in the art that in order to get uniform tablets the bulk to be tableted should be homogeneous and should have good flow characteristics.

WO97/30699 (Boots) described tablets containing 35% or more ibuprofen medicament (typically ibuprofen sodium dihydrate) and which contain an alkali metal carbonate or an alkali metal bicarbonate as auxiliary material The loading of drug described in the examples is around 50% and in one case 68.4%. WO2004/035024 (Roche) describes tablets consisting of 50-100% sodium ibuprofen hydrate and 50-0% auxiliary material component which contain no lubricant and no disintegrant. Such compositions are likely to suffer problems with tableting of sticking to tablet punches.

The art does not seem to have described a tablet of ibuprofen sodium, e.g. ibuprofen sodium dihydrate, which has high loading (therefore ensuring that tablet size is not too great), good properties in terms of the tablet itself (adequate tablet strength and rapid dissolution time) and tablet production (eg not sticking to tablet punches etc).

We have now found novel and useful pharmaceutical formulations comprising ibuprofen sodium, e.g. ibuprofen sodium hydrate, e.g. ibuprofen sodium dihydrate, which, in at least some embodiments, aim to address the above described deficiency in the art.

BRIEF DESCRIPTION OF THE INVENTION

According to the invention, we provide a novel formulation comprising dry- granulated granules produced from a powder comprising at least 60% of ibuprofen sodium. Suitably the powder comprises at least 80% eg at least 90% eg at least

95% of ibuprofen sodium. Most suitably the powder comprises 100% ibuprofen sodium. Suitably, the ibuprofen sodium is present in the formulation as a hydrate.

Most suitably, the ibuprofen sodium is present as a dihydrate. The formulation exhibits quick dissolution time. The formulation may be produced using a process where a compaction force, suitably a low compaction force, is applied to the powder comprising ibuprofen sodium to produce a compacted mass comprising a mixture of fine particles and granules. Fine particles and/or small granules are separated and removed from the granules by entraining the fine particles and/or small granules in a gas stream. The method will typically further comprise the step of collecting the granules. As explained below, the method may typically be run as a continuous process.

Suitably the process is carried out in the substantial absence of liquid.

The powder, comprising ibuprofen sodium and possibly also excipients usable in pharmaceutical industry, to be used in the formulation of the invention, generally comprises fine particles. Further, the powder may typically have a mean particle size of less than 100, 50 or 20 micrometers. The fine particles in the powder may typically have a minimum particle size of 0.1 , 1 , 5 or 10 μm and maximum size of 150, 100 or 75 μm.

The mean particle size may be measured for example using a set of sieves. In case of very fine powders, also microscopy may be used for analyzing the particle sizes. The flowability of such powders is generally insufficient for e.g. tableting purposes. An exemplary method for determining sufficient flowability of a mass is disclosed in the detailed description of figure 6.

Hence "fine particles" or "fines" are individual particles typically having a mean particle size of less than 100, 50 or 20 micrometers and a maximum size of 150, 100 or 75 μm.

When several fine particles (e.g. 3, 5, 10 or more) agglomerate to form granules of maximum size of 150, 100 or 75 μm, they are referred to as small granules. Granules larger than the maximum size are referred to as "acceptable granules". Those granules that remain after fine particles and/or small granules have been entrained by the gas stream, are called "accepted granules".

Suitably the compaction force may be provided using a roller compactor. Alternatively it may be provided using a slugging device. Other means of applying compaction force will be known to the skilled person. The roller compactor or slugging device may be accompanied by an optional flake crushing screen or other device, e.g. oscillating or rotating mill, suitable for producing granules from the compacted material. The optional step of employing a flake crushing screen or other device, will, if necessary, prepare the material for separation of fine particles and/or small granules from other granules.

Thus typically the compaction force is applied to the powder by a process comprising use of a roller compactor to generate a ribbon of compacted powder which is broken up to produce granules e.g. by means of a flake crusher. The flake crusher or similar device may permit the upper size of granules to be controlled e.g. by passing them through a screen. The aperture size of the flake crushing screen may be e.g. 0.5mm, 1.0mm or 1.2mm.

The compaction force may be adjusted to be at minimum such that at least one, five, ten or fifteen per cent of the powder substance becomes acceptable granules during compaction and/or fractionating steps, while the rest of the material remains fine particles and/or small granules.

Suitably the compaction force is a low compaction force.

If the compaction force used is too low, inventors have observed that the granules accepted by the process may be too fragile for e.g. tableting purposes. Such granules may also be too large, e.g. larger than 3 mm. Fragile granules may not flow well enough or be strong enough to be handled e.g. in a tableting process.

The maximum compaction force may be adjusted so that 75 per cent or less, 70 per cent or less, 65 per cent or less, 50 per cent or less or 40 per cent or less of the powder is compacted into acceptable granules and the rest remains as fine particles and/or small granules. The maximum compaction force is typically up to 500%, 250% or 150% of a minimum compaction force.

For example the mean particle size of the powder may be less than Y μm and the compaction force may be sufficiently low that 75% or less by weight of the powder is compacted into acceptable granules having particle size larger than 1.5 x Y μm and at least 150 μm and the rest remains as fine particles and/or small granules. For instance the mean particle size of the powder may be between 1 and 100 μm and the compaction force is sufficiently low that 75% or less by weight of the powder is compacted into acceptable granules having particle size larger than 150μm (and/or a mean size of 100μm or greater) and the rest remains as fine particles and/or small granules.

The mean particle size may be determined e.g. by dividing the bulk into a plurality of fractions using a set of sieves and weighing each of the fractions. Such measuring methods are well known to a person skilled in the art.

When the compaction force is applied by a roller compactor, the compaction force may be such that the ribbon produced by the roller compactor has a tensile strength of around 40-250N i.e. at least 4ON, 5ON or 6ON and less than 250N, 200N or 150N when the thickness of the ribbon is about 4mm. The area of the measured ribbon may be e.g. 3cm x 3cm. The tensile strength of the ribbon may be measured e.g. using device of make MECMESIN™ (Mecmesin Limited, West Sussex, UK) and model BFG200N.

The compaction force may also be such that the bulk volume of the powder is reduced by around 7-40% i.e. at least 7%, 10% or 13% and less than 40%, 35% or 30% following compaction.

The maximum and minimum compaction forces will of course depend on the particular compactor used. Thus, for example the minimum compaction force may be adjusted so that it is the minimum possible compaction force, 15 kN, 20 kN or 30 kN in a Hosokawa™ (Osaka, Japan) Bepex Pharmapaktor L200/50P roller compactor. The maximum compaction force may also be adjusted so that it is 8OkN or less, 7OkN or less, 60 kN or less or 45 kN or less in a Hosokawa™ Bepex Pharmapaktor L200/50P roller compactor. For ibuprofen sodium dihydrate, compaction force of 40 kN was observed to be one possible suitable force. The inventor speculates that with this material, higher compaction force might produce better granules but the very low melting point prevents use of such compaction forces. Use of a cooling system in the granulator might be advantageous in this case.

Typically a suitable compaction force is 6OkN or less e.g. 45kN or less. Typically, a suitable compaction force is 12kN or more e.g.16kN or more in a Hosakawa Bepex Pharmapaktor L200/50P compactor or equivalent.

The compaction force may be adjusted using a method appropriate for the compactor employed, for example by control of the rate of feed into the compactor.

The above mentioned preferred compaction forces are low and, as explained elsewhere herein, granulate mass compacted using such low forces and processed according to the invention appears to retain good properties of compressibility into tablets.

The gas stream may be provided by any suitable means, e.g. a generator of negative pressure i.e. a vacuum pump such as a suction fan. The gas stream, e.g. air, may be directed through a fractionating chamber. The gas stream separates at least some fine particles and/or small granules from the mass comprising acceptable granules, small granules and fine particles. The separated fine particles and/or small granules entrained in the gas stream may be transferred from the fractionating chamber to a separating device, e.g. a cyclone where the carrier gas is separated from the fine particles and/or small granules. The fine particles and/or small granules may then be returned to the system for immediate re-processing (i.e. they are re-circulated for compaction) or they may be placed into a container for later re-processing.

Thus, conveniently, fine particles and/or small granules are separated from the acceptable granules by means of an apparatus comprising fractionating means. Desirably, the fractionating means comprises a fractionating chamber. As discussed in greater detail in the examples, the largest acceptable granules exiting from the fractionating chamber are usually larger in size than the largest granules entering the fractionating chamber. The inventors believe that a process whereby small granules and/or fine particles agglomerate with larger granules takes place during the conveyance of the material through the fractionating chamber.

Suitably the direction of the flow of the gas stream has a component which is contrary to that of the direction of flow of the compacted mass in general and accepted granules especially. Typically the direction of the flow of the gas stream is substantially contrary to (e.g. around 150-180° to), and preferably contrary to that of the direction of flow of the compacted mass.

The gas may, for example, be air (suitably dry air). In some embodiments, the gas may contain a reduced proportion of oxygen. In some embodiments, the gas may be e.g. nitrogen.

The carrier gas may suitably be re-circulated in the process. This is especially beneficial for economic reasons when the carrier gas is not air.

The fractionating means may be static, i.e. it comprises no moving parts. Alternatively the fractionating means may be dynamic, i.e. the fractionating means comprises some moving parts.

In a method according to the invention fine particles and/or small granules may be separated and removed from the granules by means of an apparatus comprising two or more (eg two) fractionating means in series. In some embodiments, the arrangement may comprise a plurality of static and/or dynamic fractionating means that may be arranged in parallel or in series. In one embodiment, a dynamic fractionating means may be connected in series to a static fractionating means. The fractionating means may comprise means to guide a gas stream into the fractionating means, means to put the compacted mass into motion and means to guide removed fine particles and/or small granules entrained in the gas stream from the fractionating means, e.g. for re-processing. The compacted mass may be put into motion simply by the effect of gravitation and/or by mechanical means.

A number of fractionating means are known which may be suitable for use in performance of the invention. The fractionating means may for example comprise a moving device e.g. a rotating device, such as a cylinder (or cone), along the axis of which the compacted mass is moved in the gas stream. Movement of the compacted mass may be by gravitational means or may be facilitated by mechanical means, or by features of the device (e.g. cylinder). The rotating device may comprise at least one structure for guiding the compacted mass inside the rotating device, such as by provision of a spiral structure. The spiral structure may be formed of channels or baffles which guide the movement of the compacted mass. A component of gravitational assistance or resistance may be provided by tilting the axis of the rotating device. Suitably the compacted mass moves along a helical path within the device. This is advantageous since it increases the path length of the compacted mass and thereby the residence time in the device, and this is expected to increase the efficiency of fractionation. Suitably the length of the helical path is at least twice the linear length of travel along the axis of the device, e.g. at least 2, 3 or 5 times. Suitably there is also at least some movement of the compacted mass relative to the device itself which may thereby create some friction between the mass and the wall of the device. The friction may contribute to the thboelectrification phenomenon that may occur in the fractionating device and/or possibly in the pneumatic conveyor tubes of the system. Suitably the first orifice is provided with valves (e.g. flaps) so that carrier gas does not exit through it.

Advantageously the fractionating means does not require passage of the compacted mass through any sieve (such as a mesh screen). Sieves have a tendency to break up lightly compacted granules, therefore avoidance of use of a sieve permits lightly compacted granules, with their favorable properties, to be preserved e.g. for tableting. Moreover sieves are easily clogged, which disrupts the process, especially when run in continuous operation. Additionally, the eye size of a sieve may vary during the period of operation due to transient clogging.

The fractionating means may contain apertures through which fine particles and/or small granules are entrained. In one specific embodiment of the invention the gas stream enters the rotating device along its axis (in the opposite sense to movement of the compacted mass) and exits the rotating device through apertures (perforations) in the side walls of the rotating device.

As noted above, the fractionating means may comprise a moving device, e.g. a rotating device to move the compacted mass in the fractionating means. The moving device may comprise one or more apertures through which the gas stream flows into and out of the moving device and through which the fine particles and/or small granules are entrained. The apertures through which gas flows out of the device may be substantially larger than rejectable fine particles, e.g. at least 50%, 100% or 150% of the average diameter of accepted granules. In absolute terms, the apertures may for example have a minimum dimension of around 250 μm, 500 μm or 750 μm or more. This helps prevent the apertures from clogging even when relatively high volumes of fine particles of possibly sticky material need to be separated from the compacted mass. In this sense, the moving device significantly differs from an air sieve of the prior art where the sieve mesh size must be of about the same size as the largest rejected particle. Instead of relying on the mesh size in the sieving, the fractionating device of the invention relies on the gas stream's ability to entrain fine particles from the moving compacted mass. The determination of the size of acceptable granules is achieved by balancing their gravitational force (together with other forces, e.g. mechanical and centrifugal forces) against the force of the gas stream.

In another embodiment, the fractionating means may comprise a cylindrical device having a first orifice at the top of the device for entry of material from the compactor, a second orifice at the bottom of the device for exit of accepted granules as well as entry of carrier gas and a third orifice for exit of carrier gas located at or near the top of the device and above the first orifice. In use the compacted powder enters the device through the first orifice and passes through the device under the influence of gravitation and the carrier gas enters and exits the device through the second and third orifices respectively. The accepted granules leave the device through the second orifice. The rejected fine particles and/or small granules are carried by the carrier gas through the third orifice. The third orifice is orientated above the first orifice so that no component of the compacted mass may leave the device through the third orifice without having been entrained contrary to the influence of gravitation (i.e. the compacted mass does not just pass from the first orifice to the third orifice without residing in the device for any significant length of time). Suitably the first orifice is provided with valves (e.g. flaps) so that carrier gas does not exit through it.

In another embodiment, the fractionating means may comprise a device having a frustoconical lower section and optionally a cylindrical upper section and having a first orifice at the top of the device for entry of material from the compactor, a second orifice at the apex of the frustoconical section for exit of accepted granules as well as entry of carrier gas and a third orifice for exit of carrier gas orientated tangentially to the perimeter of the device and above the first orifice. In use the compacted powder enters the device through the first orifice and passes through the device under the influence of gravitation and the carrier gas enters and exits the device through the second and third orifices respectively causing a vortex effect to be created within the device. Such a device may be referred to as a vortex device. The accepted granules leave the device through the second orifice. The rejected fine particles and/or small granules are carried by the carrier gas through the third orifice. The third orifice is orientated above the first orifice so that no component of the compacted mass may leave the device through the third orifice without having been entrained contrary to the influence of gravitation (i.e. the compacted mass does not just pass from the first orifice to the third orifice without residing in the device for any significant length of time). In this embodiment, the compacted mass (or at least components of it) follows a helical path through the device due to creation of the vortex. Suitably the length of the helical path is at least twice the linear length of travel along the axis of the device, e.g. at least 2, 3 or 5 times. There may also be friction between the mass moving in the vortex and the stationary wall of the device. The friction may contribute to the thboelectrification phenomenon possibly occurring in the fractionating device. Suitably the first orifice is provided with valves (e.g. flaps) so that carrier gas does not exit through it.

Suitably the fractionating means is provided with means to prevent clogging or build-up. For example it may be provided with a vibrating or ultrasound emitting means. Alternatively when the fractionating means contains apertures (eg in the case of a rotating cylinder with one or more apertures) said apertures may be unclogged by blowing pressurized gas eg air through or across the apertures.

Some of the fine particles and/or small granules may be agglomerated to other granules in the fractionating means and/or in the pneumatic conveying means by means of the individual or combined influence of the carrier gas stream, mechanical forces, attractive forces and electrostatic forces, for example. Thus, the process may produce granules that are larger than what is produced by the flake crushing screen of the system. In some embodiments, the degree of agglomeration of the compacted mass in the fractionating phase may be significant.

The movement of the mass in the gas stream may be achieved by applying, for example, a mechanical force, gravitational force, centrifugal force or a combination of these. In some embodiments, a mechanically moving component in the fractionating means may not be needed at all to realize the benefits of the present invention. In some embodiments, the acceptable granules fall in a gas stream e.g. by effect of gravitation force and unacceptable particles and granules are moved to at least partially opposite direction by the gas stream. Suitably, however, the compacted mass is moved in the gas stream by means including mechanical means.

Typically the average residence time of the compacted mass within the fractionating means is at least 2 seconds, perhaps even at least 5 seconds, although the desired fractionating effect (including any agglomerating effect) may be achievable also in a time frame shorter than that. Residence time may be extended e.g. by providing a helical path.

It should also be noted that the rejected fraction of the mass may also contain acceptable granules. By allowing some recycling of acceptable granules the overall apparatus may be made e.g. more efficient and easier to maintain as clogging of fractionating device may be more easily avoided. These rejected acceptable granules may be conveyed to the beginning of the granulating process along with the other rejected material for reprocessing. For efficiency, we prefer that at maximum 30, 45, 60 or 75 per cent of acceptable granules are re-cycled with the fines. The inventors have not observed any detrimental effect on the granulate mass caused by recycling. This may be attributable to the use of low compaction force.

The formulation of the invention may be achieved using an apparatus comprising compacting means and means adapted to separate fine particles and/or small granules from a compacted mass by entraining the fine particles and/or small granules in a gas stream, e.g. air.

Thus an apparatus usable to manufacture the formulations of the invention may be characterized in that said fractionating means for example comprising a rotating device (see e.g. (401 ) in the drawings) comprises at least one exit aperture (see e.g. (511 ) in the drawings) through which said gas stream flows out of said means said aperture being large enough to allow a granule having acceptable properties (e.g. flowability, tablettability, size, especially size) to flow out of said device. The apparatus may further comprise a separating means (e.g. a cyclone) to separate the gas stream from the particles removed from the compacted mass.

The apparatus suitable for producing embodiments of the formulation of the invention may be characterized in that the apparatus comprises compacting means capable of producing compaction force and fractionating means adapted to separate fine particles and/or small granules from a compacted mass by entraining the fine particles and/or small granules in a gas stream. The apparatus may suitably comprise a roller compactor to generate a ribbon of compacted powder which is then broken up to produce granules. Said apparatus may be characterized in that said fractionating means comprises means to move said compacted mass. Said means to move said compacted mass may comprise means to move said compacted mass by gravitational or mechanical means. The fractionating means may further comprise at least one structure (see e.g. (403) in the drawings) for guiding said compacted mass inside said fractionating means.

The apparatus may further comprise means to provide the gas stream wherein the direction of the flow of the gas stream has a component which is contrary to that of the direction of flow of the compacted mass (e.g. the direction of the flow of the gas stream is substantially contrary to that of the direction of flow of the compacted mass).

An apparatus usable to manufacture formulation of the invention is typically provided with a fractionating means which comprises a rotating device (e.g. a cylinder or cone, especially a cylinder) along the axis of which the compacted mass is moved in said gas stream. Movement of the compacted mass along the axis of the rotating device may be facilitated by means of a spiral structure which guides the movement of the compacted mass. The fractionating means e.g. the rotating device may contain apertures through which the fine particles and/or small granules are entrained. When it is desired to produce granules of mean size x, the apertures may have a minimum dimension of 0.5x, or 1.0x or even 1.5x. In absolute terms the apertures may, for example, have a minimum dimension of 250μm, 500μm or 750μm.

The apparatus typically comprises a fractionating device adapted to separate fine particles and/or small granules from a compacted mass by entraining the fine particles in a gas stream which comprises a rotating device, such as a cylinder or cone, along the axis of which the compacted mass is moved in said gas stream and which rotating device contains apertures through which fine particles and/or small granules are entrained.

The fractionating device may comprise a fractionating chamber there being, mounted inside the chamber, an open ended cylinder (or cone). The open ended cylinder (or cone) may be rotatably supported on rollers. Carrier gas is supplied to the inside of the open ended cylinder (or cone). The jacket of the cylinder (or cone) may be perforated with apertures through which fine particles and/or small granules are entrained in the carrier gas. As described elsewhere, the entrained fine particles and/or small granules may be captured for recycling.

In the method according to the invention, pneumatic transport may be used. Suitably, the gas used to entrain the fine particles in the compacted mass is in fluid communication with the carrier gas used to transport materials in continuous operation.

Thus, suitably the powder for compaction is conveyed from a reservoir to the means to apply compaction force by means comprising use of a pneumatic conveyor.

The pneumatic transport may use a device, e.g. a cyclone, for separating carrier gas from fine particles. The device may be for example capable of continuous operation at an about even gas flow rate, in the sense that the carrier gas stream used in the fractionating process is not disturbed by pressure changes, e.g. by pressure shocks, such as are required to keep filters of various types open. The carrier gas stream(s) used in the fractionating process and/or the pneumatic conveyance (which suitably are one and the same gas stream) are suitably created by a generator of negative pressure (e.g. a vacuum pump) which draws gas in from another part of the system, typically at the outlet to the fractionating means. A suction fan is a typical example of a vacuum pump. The vacuum pump is suitably provided with at least one filter to capture any particles that without filtering would be drawn through the pump. Most suitably two filters are provided in series (i.e. a receiver filter and a safety filter).

"Continuous operation" in this context means ability to operate without maintenance or other interruptions for at least one hour, eight hours or 24 hours.

One aspect of the invention is a dry-granulate mass containing granules obtainable according to the method of the invention.

According to the invention, we also provide a granulate mass, wherein the granules comprising at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% or 90% or 95% of ibuprofen sodium, e.g. ibuprofen sodium dihydrate, may have a mean granule size of more than 50, 100, 200 or 500 micrometers, maximum granule size of 3, 2 or 1 millimeters and good flowability. In some embodiments, the granulate mass comprises 100% of ibuprofen sodium. The granulate mass exhibits good solubility to water. The mass may alternatively or additionally have at least one, two, three or four of the following properties: substantial absence of solid bridges between particles within the granule, good homogeneity, porous structure of the granules, substantial proportion of small granules and/or fine particles in the mass (typically associated with other granules), good compressibility and tabletability. Suitably the granules have a mean granule size of more than 100 micrometers and a maximum granule size of 3 millimeters.

Good solubility to water (quick dissolution time) may mean for example that 50%,

80% or 90% of the ibuprofen sodium of the granules or tablets manufactured from the granules dissolves within 15, 10, 5, 2 or 1 minutes when put into water of approximate body temperature or into the human gastric system. The quick dissolution time is attributable to the observation that the novel granulation method described herein does not significantly alter the chemical properties of the powder substance. Thus, the favorable dissolution characteristics of unprocessed ibuprofen sodium powder are transferred to the granular mass and further to the tablets manufactured from the granular mass. The formulation of the present invention discloses granules and tablets of ibuprofen sodium that provide many generally desirable characteristics of granules (e.g. flowability) and tablets (e.g. disintegration time) without deteriorating the valuable characteristics of the active pharmaceutical ingredient (e.g. quick dissolution time).

Most desirable characteristics of the granulate mass are typically quick dissolution time, good flowability, good tabletability, good homogeneity, porous structure of the granules, substantial proportion of small granules and/or fine particles in the mass.

To analyze particle size of a granulate mass, a stack of for example four sieves may be used where opening sizes of the sieves are for example 850μm, 500μm, 250μm and 106μm.

The mean granule size of material accepted by fractionating means may be calculated as the geometric mean of the diameter openings in two adjacent sieves in the stack.

d, = (d_u x αf_o)^{0 5}

where d, = diameter of i^th sieve in the stack d_u = diameter opening through which particles will pass (sieve proceeding i^th) d_o = diameter opening through which particles will not pass (i^th sieve). Because it is not practical to count each particle individually and calculate an average, the average particle size can be calculated on a weight basis. This can be done for example with the following equation:

d_gw = log^"1 [∑ (W₁ log of,)/ ∑ W]

The standard deviation can now be calculated as follows:

S_gw = log^"1 [∑W, flog d, - log d_gw) ²1 ∑W]° ⁵

More detailed description of the exemplary size analysis method shown here is available in an article "Scott Baker and Tim Herrman, Evaluating Particle Size, Kansas State University, May 2002."

It should be born in mind that when the particle size of the granulate mass is analyzed by the above method, at least some of the coating particles / small granules may be detached from the compressed core.

Flow characteristics, e.g. good flowability, may be determined using an open- ended cone having a round opening in the narrower end of the cone, e.g. a filter funnel. One set of such cones and related test method is described in more detail with respect to figure 6.

Substantial absence of solid bridges in the granule structure means for example structure where less than 30% or 10% of particles of the granule are kept together with solid bridges on average. Presence of solid bridges in the granule structure may be analyzed for example using a scanning electron microscope. With such device, it may be possible to identify individual fine particles in the granulate structure as well as visible solid bridges such as crystallized structures between the particles of the granule. Good homogeneity in this context may mean for example a granulate mass that consists of granules whose standard deviation from mean granule size is less than 2.5, less than 2.25 or less than 2.0. Inventors further believe that the homogeneous characteristics of the granulate mass of embodiments of the invention may have at least partially be achievable by the porous structure of the granules. Because of the homogeneous characteristics of the mass, the mass may be conveyed in the manufacturing process without any significant segregation of material. Yet further, good homogeneity of the granular mass may contribute to the good tabletability of the mass e.g. as demonstrated by less susceptibility to the capping phenomenon.

The structure of the accepted granules, and especially a coating layer, may be generally porous, i.e. dense granules may be substantially absent in the granulate mass. The core of the granule is expected to be porous due to the use of low compaction force. Porous structure of the granule may alternatively or additionally mean, for example, that the surface of the granule may be observed to comprise pores and/or loosely attached small granules and/or fine particles of size of approximately at least 1 , 2 or 5 micrometers and less than 150, 100 or 50 micrometers.

Substantial absence of dense granules means that less than 20 or 10 per cent of the resulting mass weight is dense granules. Dense granule is e.g. a granule whose surface appears to be a compressed, non-porous one.

The granulate mass may also comprise a substantial proportion of small granules and/or fine particles, possibly forming a coating layer on larger granules which is loosely attached e.g. via electrostatic forces. A substantial proportion of small granules and/or fine particles may be more than 2%, 5% or 10% of the overall weight of the granulate mass. Presence of small, preferably porous granules and/or fine particles may contribute positively e.g. to the flowability and compressibility of the granulate mass. This may for example lead to an improved tensile strength and/or more rapid disintegration time of a tablet compressed from the granulate mass. Surprisingly, and contrary to what is taught in the prior art, e.g. in WO99/11261 , the substantial proportion of small granules and/or fine particles in the granulate mass of the invention does generally not seem to affect the flowability of the granulate mass in any significant negative manner.

Without being limited by theory, the inventors believe that the product of the process of the invention is influenced by triboelectric effects caused by passage of powder through the system, e.g. through the fractionating device and/or through the pipeline of the pneumatic conveyor. It is suggested in prior art that small particles may have a tendency to develop a negative charge whereas larger particles develop a positive charge (or at least a less negative charge) (see e.g. article "Generation of bipolar electric fields during industrial handling of powders" by Ion. I. lnculet et al, Chemical Engineering Science 61 (2006), pages 2249- 2253) e.g. when conveyed by a gas stream or otherwise moved in a gas stream. Hence at least some and possibly most of the granules of the dry granule mass appear to comprise a compressed core containing fine particles of material associated by Van der Waals forces and a coating layer containing fine particles and/or small granules of said material associated with said compressed core by electrostatic forces. The small granules that are loosely attached on the surface of the compressed core may contribute positively e.g. to the tableting characteristics of the granular mass. For example, lubricant may be spread over a larger surface area around the granule than what happens with less porous granules of prior art. Therefore, more lubricant may be mixed with the API in the tableting phase without materially adversely affecting e.g. the hardness properties of the resulting tablets.

The inventors have also discovered that, at least in some cases, if granules obtained by the process disclosed herein are taken and a proportion of the starting material composed of fine particles is added back (eg up to 5, 10 or 15% fine particles is added back to a granulate mass that may already have e.g. 20% of fine particles and/or small granules) then the homogeneity, flowability and tabletability of the granulate mass may not be adversely affected in a significant manner, i.e. the flowability of the mass may still be at good level. The added fines are, perhaps, taken into the porous surface of granules formed by the process of the invention. Inventors thus believe that in some embodiments, it may be possible to use granules of some embodiments of the invention as "carrier granules" that may absorb e.g. into the pores of the granules up to 10%, 20%, 30% or more of fine particles and/or small granules comprising same or different material as the carrier granules. The flowability of such mixture may be at an excellent, very good or good level. In some embodiments of the present invention, the added material may comprise non-granulated excipients, e.g. microcrystalline cellulose.

The granulate mass is believed to have good compressibility because at least the surface of the granules is porous. The compressibility of the granulate mass of the invention may be good, i.e. it may have a Hausner ratio of greater than 1.15, 1.20 or 1.25. The compaction force of the present invention may be adjusted so that the compressibility as indicated by the Hausner ratio stays at good level.

The Hausner ratio may be calculated using formula p_tap/Pbuik where p_tap represents tapped bulk density of the granulate mass and p_bui_k represents the loose bulk density of the granulate mass. The bulk densities may be measured by pouring 50 mg of granulate mass into a glass cylinder (e.g. make FORTUNA, model 250:2 ml) having an inner diameter of 3.8mm. After pouring the mass into the cylinder, the volume of the mass is observed from the scale of the glass cylinder and loose bulk density of the mass is calculated. To measure the tapped bulk density, the glass cylinder is tapped 100 times against a table top using a force comparable to a drop from the height of 5 cm. The volume of the tapped mass is observed from the scale of the glass cylinder and tapped bulk density of the mass is calculated.

Porous, well-flowing granules are generally desired in the pharmaceutical industry for example because it is possible to produce enhanced tablets from porous granules. Such tablets may for example disintegrate substantially quicker than tablets manufactured from dense granules. Further, tablets compressed from porous granules often show higher tensile strength than tablets compressed from dense granules. High tensile strength is often desirable for tablets as such tablets are easier to package and transport than fragile tablets.

The granulate mass may be tabletable so that using standard tableting techniques, e.g. using tableting forces available in widely used tableting machines, it is possible to form it into tablets having tensile strength of at least 5N, 1 ON or 15N. Tensile strength may be measured for example using a measuring device of make MECMESIN™ (Mecmesin Limited, West Sussex, UK) and model BFG200N.

The granulate mass may comprise at least 1 %, 20%, 40%, 60% or 80% of ibuprofen sodium. In one embodiment the granulate mass comprises (eg consists of) 100% ibuprofen sodium. In another embodiment the granulate mass comprises ibuprofen sodium and at least one (eg one) excipient.

Thus the invention also provides a process for preparing a tablet which comprises compressing a dry-granulated granulate mass according to the invention optionally blended with one or more additional excipients. Said one or more additional excipients may comprise lubricant, e.g. magnesium stearate, magnesium aluminium silicate, hydrogenated oil, hydrogenated vegetable oil or hydrogenated cottonseed oil (e.g. Lubhtab™). A tablet obtainable by such a process is another aspect of the invention.

According to the yet further feature of the invention we provide a tablet comprising at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of ibuprofen sodium. In an embodiment, the tablet comprises at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of ibuprofen sodium hydrate, e.g. dihydrate. The tablet may exhibit quick dissolution time. The tablet may further have at least one, two or three of the following properties: substantial absence of solid bridges binding particles within the granules forming the tablet, high tensile strength, high drug load and quick disintegration time. The tablet may further be characterized in that the balance of the composition is one or more excipients selected from starch and starch derivatives, cellulose and cellulose derivatives and lubricants.

High drug load means that, for example, the tablet may comprise at least 40 per cent, 60 per cent or 80 per cent of API(s) of the overall weight of the tablet.

Quick disintegration time may be less than 600, 300, 120 or 30 seconds when a tablet is put into water of approximately body temperature (i.e. 37 degrees Celsius).

As may be seen from the examples, tablets of the invention which have high tensile strength may nevertheless be capable of quick disintegration in water.

High tensile strength of the tablet may be more than 45N, 3ON, 2ON or 15N, e.g. as measured by MECMESIN™ BFG200N device.

The tablet of some embodiments of the present invention may comprise at least 2%, 3%, 4% or 5% of suitable lubricant, e.g. hydrogenated vegetable oil, e.g. hydrogenated cottonseed oil (e.g. Lubhtab™). A suitable amount of lubricant is at least 2% e.g. 2-10% e.g. 2-5% w/w.

The lubricant may be distributed essentially on the porous surface of the granules of the tablet. The lubricant may for example be located essentially on the surface and in the pores of the surface of the granules forming the tablet whereas there is no or little lubricant inside the core of the granule. The lubricant may be distributed e.g so that more than 90, 80 or 70 per cent of lubricant is located in a cross- sectional area (cut surface) that is less than 10, 20 or 30 per cent of the total sectional area of a tablet. The location of the lubricant particles on a sectional area of a tablet may be observed using e.g. a system comprising scanning electron microscope and additional equipment capable of identifying especially the particles comprising lubricant material. The tablet may suitably exhibit substantially low percentage of hydrogen bonding liquid, e.g. water.

A tablet suitably exhibits substantially low percentage of liquid and/or hydrogen bonds, lubricant is unevenly distributed across the tablet and the tablet has further at least two of the following properties: quick disintegration time, high tensile strength, high drug load and significant amount e.g. at least 2%, 3%, 3% or 4% (weight), of lubricant.

The tablet of the invention may comprise excipient that comprises dry-granulated starch. For example it may comprise excipient that comprises up to 60% of dry- granulated starch.

A granulate mass or tablet of the present invention may typically comprise at minimum 1 , 5 or 10 per cent (weight) and at maximum 100, 95, 90, 80 or 70% of ibuprofen sodium. In some embodiments said powder contains an amount of primary active pharmaceutical ingredient of at least 60% e.g. at least 80%. The granulate mass or tablet may further comprise at minimum 5, 10, 20 or 30% (weight) and at maximum 99, 95 or 90% of at least one excipient, e.g. long-chain polymer e.g. starch or cellulose. The granulate mass or tablet of some embodiments of the present invention may further comprise at least 1 %, 5%, 10%, 20%, 30%, 50% or 70% of of at least one second active pharmaceutical ingredient.

To achieve quick disintegration time for a tablet that comprises at least 5, 20 or 30 per cent (weight) of ibuprofen sodium, the tablet may further comprise at minimum 1 , 3 or 5 per cent and at maximum 7, 10 or 20 per cent (weight) or more of disintegrant, e.g. crospovidone. A typical amount of disintegrant is 1 -10%. In some embodiments, the percentage of disintegrant in a tablet may be also higher than 20 per cent. In some embodiments, disintegrant is not needed (i.e. the tablet is free of disintegrant). The disintegrant may be e.g. some starch or carboxymethyl cellulose (CMC, e.g. Nymcel™) or a combination of these. The granulate mass or tablet may also comprise at minimum 1 , 5 or 10 per cent and at maximum 60, 80 or 94% (weight) of filler (diluent), e.g. microcrystalline cellulose. A typical amount of filler is 1 -20% eg 5-10%. In some embodiments filler is not needed (i.e. the tablet is free of filler). The API, disintegrant and filler may be granulated together or separately using the method of the present invention.

For improving taste of e.g. a fast disintegrating tablet (orally disintegrating tablet), up to 50, 70 or 90% of sweetener, e.g. xylitol may be included into the tablet. If necessary, the sweetener may be granulated using an embodiment of the method of present invention. Further, the sweetener may be granulated separately or together with at least one other component (API or excipient) of a formulation. We have observed that at least with some APIs, use of separately granulated sweetener (xylitol) in a tablet may result as a quicker release time in comparison to a tablet where sweetener is granulated together with other components.

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

Different kinds of end products, including tablets, oral suspensions and capsules may be manufactured from the granulate mass.

According to the invention, we also provide a process for manufacture of a tablet which comprises tableting a granule according to the invention, or a granule made using the method of the invention.

One exemplary process comprises compressing a dry-granulated granulate mass comprising 100% ibuprofen sodium dihydrate blended with a lubricant in an amount of 2-5% w/w and optionally one or more disintegrants in an amount of 1 - 10% w/w and optionally one or more fillers in an amount of 1 -20%. The formulation of the present invention may also comprise excipients or other ingredients usable in e.g. pharmaceutical industry, such as for example L- asparagic acid, wheat gluten powder, acacia powder, alginic acid, alginate, alfa- starch, ethyl cellulose, casein, fructose, dry yeast, dried aluminum hydroxide gel, agar, xylitol, citric acid, glycerin, sodium gluconate, L-glutamine, clay, croscarmellose sodium, Nymcel™, sodium carboxymethyl cellulose, crospovidone, calcium silicate, cinnamon powder, crystalline cellulose-carmellose sodium, synthetic aluminum silicate, wheat starch, rice starch, potassium acetate, cellulose acetate phthalate, dihydroxyaluminum aminoacetate, 2,6-dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid, potassium hydrogen tartrate, magnesium hydroxide, calcium stearate, magnesium stearate, magnesium aluminium silicate, hydrogenated oils, e.g. hydrogenated vegetable oil, e.g. hydrogenated cottonseed oil, e.g. Lubhtab™, purified shellac, purified sucrose, D-sorbitol, skim milk powder, talc, low substitution degree hydroxypropylcellulose, dextrin, powdered tragacanth, calcium lactate, lactose, sucrose, potato starch, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, glucose, partially pregelatinized starch, pullulan, powdered cellulose, pectin, polyvinylpyrrolidone, maltitol, maltose, D- mannitol, anhydrous lactose, anhydrous calcium hydrogenphosphate, anhydrous calcium phosphate, magnesium aluminometasilicate, methyl cellulose, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, medicinal carbon, granular corn starch, dl-malic acid and possibly other such others classified as excipient in Arthur H. Kibbe: Handbook of Pharmaceutical Excipients, 3^rd Edition, and one, two or more of them in combination.

The formulation of the present invention may also comprise disintegrants such as for example carboxymethyl cellulose, Nymcel™, sodium carboxymethyl cellulose, croscarmellose sodium, cellulose such as low substitution degree hydroxypropylcellulose, starch such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, potato starch, maize starch, partly pregelatinized starch, crospovidone and others classified as disintegrators in Arthur H. Kibbe: Handbook of Pharmaceutical Excipients, 3^rd Edition, and one, two or more of them in combination. The formulation of the present invention may also comprise binders such as for example synthetic polymers such as crospovidone, saccharides such as sucrose, glucose, lactose and fructose, sugar alcohols such as mannitol, xylitol, maltitol, erythritol, sorbitol, water-soluble polysaccharides such as celluloses such as crystalline cellulose, microcrystalline cellulose, powdered cellulose, hydroxypropylcellulose and methyl cellulose, starches, synthetic polymers such as polyvinylpyrrolidone, inorganic compounds such as calcium carbonate and others classified as binders in Arthur H. Kibbe: Handbook of Pharmaceutical Excipients, 3rd Edition, and one, two or more of them in combination.

According to another aspect of the invention, we provide a granulate mass, characterized in that the mass is tabletable and that the granulate mass has good flowability and that the mass comprises at least 5% of ibuprofen sodium.

According to another aspect of the invention, we provide a tablet, characterized in that the tensile strength of the tablet is at least 2ON and the tablet is manufactured from dry-granulated granules comprising at least 5% (weight) of ibuprofen sodium.

According to another aspect of the invention, we provide a tablet formed by compression of a dry granulate mass comprising 5% or more of ibuprofen sodium. The tablet may exhibit quick dissolution time. The balance of the composition of the dry granulate mass may, for example be one or more lubricants, fillers and/or disintegrants selected from starch, cellulose and cellulose derivatives and suitable lubricants, e.g. hydrogenated vegetable oil or magnesium aluminium silicate. In some embodiment, the tablet comprises at least 40%, 60%, 80%, 90% or 95% of ibuprofen sodium, e.g. ibuprofen sodium dihydrate, and at least 2%, 3%, 4% or 5% of lubricant, e.g. hydrogenated vegetable oil, e.g. hydrogenated cottonseed oil (e.g. Lubritab™)

According to another aspect of the invention, we provide a tablet formed by compression of a dry granulate mass comprising (i) granules comprising 20%,

40%, 60%, 80% or more (e.g. 90% or 95% or more e.g. 100%) of ibuprofen sodium, e.g. ibuprofen sodium dihydrate, and (ii) granules comprising one or more fillers and/or disintegrants selected from starch, cellulose and cellulose derivatives. In either case a lubricant may optionally be blended with the dry granulate mass before compressing it into tablets.

Exemplary tablets are:

A tablet characterized in that the tablet comprises at least 20% of ibuprofen sodium dihydrate and wherein the balance of the composition is one or more excipients selected from starch and starch derivatives, cellulose and cellulose derivatives and lubricants. A tablet consisting of (a) at least 95% ibuprofen sodium dihydrate (b) 2-5% lubricant.

A tablet consisting of (a) at least 80% eg at least 90% eg at least 95% ibuprofen sodium dihydrate (b) 2-5% lubricant and (c) 1 -10% disintegrant.

A tablet consisting of (a) at least 80% eg at least 90% eg at least 95% ibuprofen sodium dihydrate (b) 2-5% lubricant (c) 1 -10% disintegrant and (d) 1 -20% filler.

Suitably tablets according to the invention are free of alkali metal carbonates or alkali metal bicarbonates.

In some embodiments, the tablets may disintegrate and/or dissolve in water of approximately body temperature, i.e 37 degrees Celsius, in less than 300 or 120 or 60 seconds. For quick disintegrating tablets, the API suitably does not exceed 98% of the tablet composition and the composition may contain at least 2% of disintegrant. The tablets suitably have a tensile strength of greater than 2ON. In one embodiment the tablets may comprise xylitol in an amount of 90% or less.

Some embodiments of the invention are described herein, and further applications and adaptations of the invention will be apparent to those of ordinary skill in the art.

BRIEF DESCRIPTION OF DRAWINGS In the following, the invention is illustrated, but in no way limited by reference to the accompanying drawings in which

Fig. 1 a and Fig. 1 b show exemplary apparatuses suitable for producing formulations of various embodiments of the invention,

Fig. 2a shows use of roller compactor according to an embodiment of the invention,

Fig. 2b shows use of roller compactor producing both avoidable dense (according to prior art) and desirable porous granules,

Fig. 3 shows an exemplary fractionating device according usable in an embodiment of the invention,

Fig. 4 shows an exemplary fractionating device that contains an additional rotating device usable in an embodiment of the invention,

Fig. 5a an exemplary cylindrical component that can be used in the fractionating device shown in figure 4,

Fig 5b shows an exemplary perforated steel sheet that may be used as part of a rotating device of figure 4,

Fig. 6 shows an exemplary device for determining flowability of a powder or granulate mass.

DETAILED DESCRIPTION OF DRAWINGS

The apparatus 100 (figures 1 a and 1 b) suitable for producing granules of an embodiment of the invention comprises a compacting device that compacts powder material into granules and a fractionating device that fractionates at least some fine particles and/or small granules away from acceptable granules. Two different alternatives for a fractionating device are shown in figures 1 a and 1 b. The fractionating device 112 in figure 1 a is shown in more detail in figure 3. The fractionating device 112 in figure 1 b is shown in more detail in figure 4. The apparatus shown in fig. 1 a and fig. 1 b comprise a raw material feeding container 101 , into which material to be granulated is fed. The feeding container is connected to a pneumatic conveyor pipeline 102, to which the material is passed through a feeder valve 103. Thboelecthfication of the material may occur in the conveyor pipeline. The tubes of the pneumatic conveyor system have a diameter of about 47mm. The feeder valve may be a so-called star-shape flap valve. One such valve is manufactured by Italian pharmaceutical device manufacturer CO.RA™ (Lucca, Italy). In operation, the closing element of the valve may be turned 180° alternately in either direction, whereby buildup of the powder substance in the container can be avoided. Other equipment intended for continuous charging of powder substance, such as compartment feeders, may also be used.

The pressure of the air flowing within the conveyor 102 may be adjusted to be lower than that of the surroundings. This may be achieved for example using an extractor suction fan 104. The suction fan is of make BUSCH™ (Maulburg, Germany) and model Mink MM 1202 AV. The fan may be operated for example at 2100 Hz. Makeup carrier gas may be supplied through a connection 105. The material fed from the feeding container is transported through the conveyor 102 into a separating device 106, wherein fine rejected particles and new feed from container 101 are separated from the carrier gas. The fan can be provided with filters situated beside the separating device. The device may be capable of continuous operation. One such device is a cyclone. After the separating step, the separated powder falls into an intermediate vessel 107.

The container 107 can be mounted on load cells 108 to measure the weight of the material. The intermediate vessel 107 is provided with a valve 109 which may be of the same type as the feeding container valve 103. From the intermediate vessel 107, the powder is transferred to a compacting device, e.g. roller compactor 110 to produce a ribbon of compacted material which is then passed to a flake crushing screen 111 where granules are created by crushing the ribbon. In the context of this disclosure, compacting is considered as the step of the process that produces granules to be fractionated, regardless of whether a separate screen or milling device 111 is used or not. The compaction force of the compactor 110 may be adjusted by e.g. altering the feed rate of the powder substance, the rotating speed of the rolls of the roller compactor, the pressure applied to the rolls of the compactor device and/or the thickness of the resulting ribbon. The compaction force applied by the compactor may be adjusted to a low level to achieve the desired properties of the compacted mass, e.g. the porosity of the resulting granules and/or proportion of fine particles and/or small granules. The compactor and the flake crushing screen are devices well known to a person skilled in the art. After passing the compacting and flake crushing devices, the material is partially in the form of granules, but part of the material will still be in the form of fine particles and/or small granules. The maximum size of the granules as well as the mean size of the granules may be affected by, for example, the mesh size of the flake crushing screen. It should be noted, however, that size of a granule may increase as result of agglomeration in the fractionating and/or conveying steps of the process.

In some embodiments (not shown in figure), the apparatus 100 may comprise more than one compacting device, e.g. roller compactor, to improve e.g. capacity and/or continuous processing capabilities of the apparatus. The compacting devices may require some periodic service breaks e.g. for cleaning up. The apparatus 100 may continue operation even if one of the compacting devices is being serviced.

The product from the above steps that contains fine particles and porous granules and that may be statically charged (e.g. by triboelecthfication) is conveyed to a fractionating chamber 112. There may be one or two e.g. star-shaped flap valves between compacting device and fractionating device to control the flow of compacted material to the fractionating device. The fractionating device divides the granulate mass into an accepted fraction and a rejected fraction on the basis of how different particles of the mass are affected by the carrier gas stream that flows in the fractionating device. The rejected fraction passes with the fed carrier gas stream to the feed conveyor 102, for re-processing, and the accepted fraction is led into a product container 113. By this means the product granules are treated gently and a relatively large volume of material comprising mostly fine particles and/or small granules is removed from the mass.

The operation of the fractionating chamber 112 is described in more detail with reference to Figures 3-5. There are many possible alternative fractionating devices.

In the embodiments shown in Figure 1 a and Figure 1 b, load cells 108 are fitted to the container 107. Such sensors and other instrumentation can also be arranged in other containers and components of the system. Not all of the possible instrumentation is shown in the figures. For example the pneumatic conveyor, if required, may be provided with at least one pressure difference sensor 114, the information from which can be used to control the operation of the apparatus.

The process described herein may also be carried out as a batch process where the reject fraction is not immediately returned to the system using the conveyor 102, but fed into a container of reject material. Such a system is not described in detail, but its construction and use will be readily apparent to those of skilled in the art.

The apparatus can be automated by transferring information received from the various sensors e.g. the pressure difference sensors 114, the load cells 108 and the valves 103 as well as information regarding the speed of rotation and the loads of the motors to a control unit and by applying appropriate control logic and control circuits in a manner known to a person skilled in the art. Control of the compaction force of the compacting device, e.g. roller compactor is particularly useful, as granule structure as well as the proportion of fine particles and/or small granules is significantly affected by the compaction force used. The compaction force depends on a number of parameters, such as the rotating speed of the rolls and the feed rate of the powder substance. For example, the higher the feed rate of the powder substance for a given roller rotation rate, the higher the compaction force will be. The material of the conveyor 102 may be e.g. PVC, e.g. FDA PVC. Various components of the system may be connected together with electric wires for grounding purposes. Suitably the entire system is grounded.

In figure 2a the roller compactor 200 compacts the mass 203 containing raw material and optionally particles recycled from the fractionating device into a ribbon 204, 205, 206 using rolls 201 ,202 that apply mechanical force to the mass to be compacted. Depending on the compaction force applied to the mass and the thickness of the ribbon, the amount of mass that gets compacted into granules 204, 205 varies. The remaining mass 206 may remain small granules and/or fine particles example in the middle of the ribbon. The small granules and/or fine particles may not be capable of forming acceptable granules alone. However, the presence of such mass may have a positively contributing role in forming of acceptable granules in the fractionating and/or conveying steps of the process e.g. through thboelecthfication and electrostatic forces. Depending on the feed material and compacting parameters, such as thickness of the ribbon, the proportion of fine particles and/or small granules may vary.

A convenient way to adjust operating parameters of the system is to set the compaction force of the roller compactor to the minimum that produces at least some granules and set the rotating speed (see the description related to figure 4) of the fractionating device to the maximum available (e.g. about 100 RPM) in the device of make ROTAB™ (Donsmark Process Technology A/S, Copenhagen, Denmark) and model 400EC/200 and then adjust the carrier gas flow rate so that acceptable granules with desired flow characteristics start flowing out the system. Too little gas flow in the fractionating device causes the proportion of fine particles and/or small granules to increase in the mass of accepted granules whereas use of too high a gas flow causes a large proportion of acceptable granules to be unnecessarily re-processed. Setup of the optimal gas flow may be done manually or automatically for example using real-time measurement of flow of accepted granules and characteristics of those granules. Figure 2b illustrates an example of the creation of unwanted dense granules and/or granules having solid bridges 210, 211 when a high compaction force as in the prior art is used. The more dense granules there are in the mass, the lower the quality of the mass may be for tableting. Although the flow characteristics of the mass resulting from using prior art high compaction forces (or repeated compaction with lower forces) may be acceptable even without fractionating, the compressibility and/or tabletability of the mass may with some materials be significantly lower, or some other characteristics of the tablet such as disintegration time may be undesirable. Moreover, significant heating of the material in the compaction step of prior art granulation process may be observed leading for example to formation of solid bridges through crystallization and/or degradation of components of the granules or undesirable characteristics of the granulate mass. Yet further, use of high compaction force typically reduces the proportion of small granules and/or fine particles 206 in the resulting granulate mass. Too low a percentage of such small granules and/or fine particles in the fractionating and/or conveying steps of the process may adversely affect the quality of the resulting accepted granules.

Figure 3 shows an exemplary fractionating device for removing fine particles and/or small granules from the granulate mass 303 produced by the compactor. The device has a chamber 300 that contains apertures for different purposes. The chamber may be manufactured from any suitable material, e.g. plastic. Input material 301 from the compactor and flake crusher is fed through one or multiple apertures 302. Gravity makes the material 305 flow downwards towards aperture 304 through which the accepted granulate mass 306 flows out of the system into a container. From the same aperture 304, carrier gas (air) 307 flows into the system. The gas may flow into the system also from some other aperture that is positioned such that the desired fine particle and/or small granules removing effect of the carrier gas flow is achieved. The carrier gas flows in a direction that is different from (countercurrent to) the flow of accepted granules. Accepted granules fall out of the fractionating device through tube 304 by effect of gravitation. While the granules are moving in the fractionating device 300, fine particles and/or small granules may agglomerate with other granules, thus making the granules grow further. The fine particles and/or small granules 308 are carried away from the fractionating device by the carrier gas flow 309 through aperture 310. There may be multiple apertures for the accepted granules as well as for the rejected fine particles and/or small granules.

The measures shown in figure 3 and other figures are exemplary only and are not meant to limit the invention in any manner.

Figure 4 illustrates an example of an enhanced fractionating device that may be manufactured e.g. of steel. In the figure, components and structures residing inside the device are drawn using dotted lines. The device 400 comprises a fractionating chamber and, mounted inside the chamber, an open ended cylinder (or cone-shaped device, not illustrated) 401 rotatably supported on rollers 410. The rotating speed of the cylinder can be adjusted to be for example the maximum available in the device of make ROTAB™ (Donsmark Process Technology A/S, Copenhagen, Denmark) and model 400EC/200. The jacket of the cylinder or cone may be perforated. There are no restrictions with regard to the number and shape of the possible apertures or their edges except for that the apertures should be constructed so that the gas (air) together with entrained fine particles is able to leave the cylinder through them. The apertures may be, for instance, round, oval or slots. In one embodiment, the apertures are round and they have been cut using laser cutting techniques. In one embodiment, the diameter of the round apertures is 1.5mm. A drive motor 402 is arranged to rotate the cylinder at a suitable speed, e.g. at 100 RPM. A spiral structure 403 is provided inside the cylinder for transporting the solid material from the feed end 411 to the outlet 404 as the cylinder rotates. Instead of a spiral, various kinds of fins or other structures can be provided internally within the cylinder to obtain movement of the compacted material, and its interaction with the gas stream. The angle of inclination of the cylinder may be adjusted as required by, for instance, changing the position of the whole fractionating device 400 in its suspension structure 413, 414. The powder 405 leaving the compacting device falls through a charge connection 412 into the feed end 411 of the cylinder and is transported by the spiral 403 towards an outlet tube 404. The carrier gas 406 flowing through the outlet 404 moves in the opposite direction to the accepted granules 407. Acceptable granules pass along in the cylinder 401 , and fall through the outlet 404 to a product container (not shown) by effect of gravitation. Unacceptable fine particles and/or small granules that may be accompanying the acceptable granules to the tube 404 are generally conveyed back from the tube 404 to the cylinder 401 by the gas stream 406. In the present device, the outlet 404 is a downward pointing tube whose length is 70 mm and diameter is 40 mm. The rejected fraction of fine particles and/or small granules 408 together with the carrier gas stream flows to the feeding conveyor (see 102 in figure 1 ), through connection 409 for reprocessing. The granules may grow in size in the fractionating device 400 (or 300 in figure 3). This agglomeration may be caused e.g. by triboelectrification and electrostatic forces.

The properties of the accepted fraction may be influenced e.g. by changing the rotation speed of the cylinder, the angle of inclination of the cylinder, the pitch of the spiral, and the size, number and location and the shape of the apertures in the cylinder as well as by varying the flow rate of the carrier gas. In one embodiment, a cleaning arrangement (not shown in figure) utilizing pressurized air of e.g. 1 -5 bar, preferably about 2-4 bar is used to prevent the cylinder 401 from clogging.

Figures 5a shows a cylinder-shaped device residing inside the fractionating device (see 400 in figure 4). Figure 5b shows an alternative steel sheet usable for constructing a cylinder. A cylinder 500 has apertures 501 that in the figure 5a are situated throughout the jacket of the cylinder whereas in figure 5b there are apertures only in the middle section of the cylinder. The input material 502 that contains both granules and fine particles is fed to the rotating cylinder from one end of the cylinder. The rotating movement 503 of the cylinder 500 and the spiral (see 403 in figure 4) inside the cylinder push the input material towards the other end of the cylinder. While the material is moving in the cylinder, carrier gas flow 504 separates the acceptable granules from the rejected fine particles and/or small granules 505 which are conveyed out of the cylinder through apertures 501 with the carrier gas flow. The accepted granules 506 are eventually pushed out of the cylinder by the spiral structure that resides inside the cylinder.

In the shown embodiment, the rotating device is a cylinder of diameter of 190 mm and length of 516 mm and comprises apertures each having a diameter of 1.5 mm and the apertures reside on average 6 mm from each other. The air stream that enters the fractionating device through aperture 404 (figure 4) is further led out of the fractioning chamber for reprocessing through an aperture (409 in figure 4) of 50 mm in diameter. Inside the cylinder there is a screw-shaped guiding structure that advances 80 mm per revolution towards the aperture of accepted material 506. The height of the guiding structure is 25 millimeters. Figure 5b shows a drawing of an exemplary perforated stainless steel sheet that may be used to build a suitable cylinder. The thickness of the sheet is about 0.8mm. The ROTAB™ device described above has been modified by changing the cylinder to one assembled from the steel sheet of figure 5b and the fractionating chamber has been changed to one having the shape similar to one shown in 400 of Figure 4.

Although the device shown in Figure 5a is open-ended and cylinder shaped, and the movement involved is a rotating movement, conveyor devices of other shapes and utilizing other kinds of movements may also be used to convey the mass in the fractionating air stream.

Figure 6 illustrates a simple device for measuring flowability of powder or granulate mass. Devices of different sizes are used for determining different degrees of flowability. The degree of flowability may be sufficient, good, very good or excellent.

The device for determining sufficient flowability has a smooth plastic surface cone 600 with a height 601 of 45 millimeters and with cone angle 602 of approximately 59 degrees and a round aperture 603 whose diameter is 12 millimeters. The length of tube 604 is 23mm. In a flowability test procedure, the cone is filled with powder or granulate mass while the round aperture 603 is kept closed. The aperture is opened, cone is knocked lightly to start the flow and the flow of the powder through the aperture by mere gravitation force is observed. Additional shaking or other kind of movement of the cone during the test is not allowed. The material passes the flowability test if the cone substantially empties. "Substantial" here means that at least 85%, 90% or 95% of the powder leaves the cone.

The device for determining good flowability using the test procedure explained above has a smooth glass surface cone 600 with a height 601 of 50 millimeters and with cone diameter 605 of 70mm and a round aperture 603 whose diameter is 7 millimeters. The length of tube 604 is 70 mm.

The device for determining very good flowability has a smooth plastic surface cone 600 with a height 601 of 35 millimeters and with cone diameter 605 of 48 mm and a round aperture 603 whose diameter is 4 millimeters. The length of tube 604 is 50 mm.

The device for determining excellent flowability has a smooth plastic surface cone 600 with a height 601 of 40 millimeters and with cone diameter 605 of 55 mm and a round aperture 603 whose diameter is 3 millimeters. The length of tube 604 is 60 mm.

Using the apparatus and/or method described herein, it is possible to produce granules that have one or multiple of some desirable general characteristics, e.g. good flowability, good compressibility, good tabletability, quick disintegration time of a tablet and high drug load. We have observed that those characteristics are applicable to many APIs and excipients. Thus, some potentially time-consuming and expensive parts of the drug formulation design process of prior art may be avoided with many APIs. The embodiments shown are also relatively cost-efficient to build and use. For example, it is possible to build an arrangement that is capable of producing several kilograms or tens of kilograms of granules per hour. The process is also relatively simple and easy to control in comparison to e.g. wet granulation methods of prior art. In the shown embodiments, there are few parameters that may need to be adjusted.

Percentage (%) values given herein are by weight unless otherwise stated. Mean values are geometric mean values unless otherwise stated. Mean values of particle size are based on weight.

The examples below describe characteristics of some typical granules and tablets achievable with the embodiments of the present invention.

EXAMPLES

To observe the characteristics of the granulate mass and tablets of various embodiments of the invention, a series of tests has been conducted. In all tests, method and apparatus described in this document (e.g. figure 1 b and figure 4) has been used. The gas flow rate of the apparatus was adjusted so that the fractionating effect of the gas flow resulted in a granulate mass that had good, very good or excellent flowability. The gas flow rate in the tests was achieved operating the suction fan (BUSCH™ Mink MM 1202 AV) of the system at 2100 RPM. With some materials, the speed was altered from the default to achieve desired quality of the granulate mass. The compaction force of the roller compactor was adjusted to produce granules with optimal tableting characteristics. The force used was recorded as kilonewtons as indicated by the roller compactor (HOSOKAWA Bepex Pharmapaktor L200/50P) used in the tests. The diameter of the rolls of the compactor is 200mm and the working width of the rolls is 50mm. The thickness of the ribbon produced by the compactor is about 4mm. The rotating speed of the rolls is typically between 6 and 12 RPM. When compacting ibuprofen sodium dihydrate, the rotating speed was between 6 and 8 RPM. The exact rotating speed is adjusted by the roller compactor to achieve the desired compaction force. The mesh size of the flake crushing screen is 1.00mm.

Unless specified differently, a rotating device as shown in figure 4 operating at about 100 RPM was used as the fractionating means of the apparatus of the tests. The size of apertures in the cylinder of the rotating means was 1.5mm. Pressurized air of 2 bar was used in the rotating device to prevent the cylinder from clogging. Maize starch used in the tests was estimated to have particle size between 5 and 30 micrometers.

The tensile strength of the tablets has been measured using a measuring device of make MECMESIN™ (Mecmesin Limited, West Sussex, UK) and model BFG200N.

The particle size distribution of granulate mass was measured using stack of sieves. In the measurements, the stack of four sieves was shaken for 5 minutes using an Electromagnetic Sieve Shaker (manufacturer: C.I.S.A Cedaceria Industrial, S. L, model: RP 08) with power setting 6. The opening sizes of the sieves used were 850μm, 500μm, 250μm and 106μm.

GRANULATING EXAMPLE - 100% IBUPROFEN SODIUM DIHYDRATE

4.0 kg of ibuprofen sodium dihydrate was granulated using compaction force of 40 kN into granules having mean size of 610 micrometers. Pre-pressure of about 40 kN was used in the roller compactor. 11 % of the accepted granules were smaller than 106 micrometers in diameter. The loose bulk density of the resulting granular mass was 0,476 g/ml. The flowability of the mass was observed to be excellent. The humidity of the mass was measured to be 13,84%.

TABLETING EXAMPLE 1 - 95% IBUPROFEN SODIUM DIHYDRATE

In a tableting experiment, granules of the above granulating example were used. 5% of lubricant (hydrogenated vegetable oil, Lubritab™ , JRS PHARMA GMBH & CO. KG, Batch no. 953531108) was added to the granulate mass for tableting. Tablets having dimensions of 20mm x 8mm x 4mm and average weight of 780 mg were compressed using tableting force that produced tablets having average tensile strength of 37 kN. No sticking of material to the punches of the tableting machines was detected. The disintegration time of the tablets was observed to be about 4 minutes when the tablet was put to water of approximate body temperature. As the chemical and pharmaceutical characteristics of the ibuprofen sodium dihydrate remain unchanged in the granulation and tableting process, the dissolution time of the tablet was estimated to be less than 10 minutes, e.g. 5 minutes.

TABLETING EXAMPLE 2 - 80% IBUPROFEN SODIUM DIHYDRATE

In another tableting experiment, granules of the above granulating example were used. 11 % of microcrystalline cellulose (CERESTAR), 5% of Crospovidone and 4% of lubricant (hydrogenated vegetable oil, Lubhtab™ , JRS PHARMA GMBH & CO. KG, Batch no. 953531108) was added to the granulate mass for tableting. Tablets having dimensions of 20mm x 8mm x 4mm and average weight of 740 mg were compressed using tableting force that produced tablets having average tensile strength of 48 kN. No sticking of material to the punches of the tableting machines was detected. The disintegration time of the tablets was observed to be about 4 minutes when the tablet was put to water of approximate body temperature. As the chemical and pharmaceutical characteristics of the ibuprofen sodium dihydrate remain unchanged in the granulation and tableting process, the dissolution time of the tablet was estimated to be less than 10 minutes, e.g. 5 minutes.

TABLETING EXAMPLE 3 - 40% IBUPROFEN SODIUM DIHYDRATE

In yet another tableting experiment, granules of the above granulating example were used. 51 % of microcrystalline cellulose powder (CERESTAR), 5% of Crospovidone powder and 4% of lubricant (hydrogenated vegetable oil, Lubritab™ ,JRS PHARMA GMBH & CO. KG, Batch no. 953531108) was added to the granulate mass for tableting. Tablets having dimensions of 20mm x 8mm x 3mm and average weight of 650 mg were compressed using tableting force that produced tablets having average tensile strength of 57 kN. No sticking of material to the punches of the tableting machines was detected. The disintegration time of the tablets was observed to be about 3 minutes when the tablet was put to water of approximate body temperature. As the chemical and pharmaceutical characteristics of the ibuprofen sodium dihydrate remain unchanged in the granulation and tableting process, the dissolution time of the tablet was estimated to be less than 10 minutes, e.g. 5 minutes.

To a person skilled in the art, the foregoing exemplary embodiments illustrate the model presented in this application whereby it is possible to design different methods, granules and tablets, which in obvious ways utilize the inventive idea presented in this application.

Percentage amounts employed herein are by weight unless otherwise indicated.

Claims

1. A method for producing granules from a powder comprising at least 60% w/w of ibuprofen sodium dihydrate, characterized in that compaction force is applied to the powder to produce a compacted mass comprising a mixture of fine particles and granules and separating and removing fine particles and/or small granules from the granules by entraining the fine particles and/or small granules in a gas stream.

2. A method according to claim 1 wherein the powder comprises at least 80% w/w ibuprofen sodium dihydrate.

3. A method according to claim 1 wherein the powder comprises at least 90% eg at least 95% w/w ibuprofen sodium dihydrate.

4. A method according to claim 1 wherein the powder comprises 100% ibuprofen sodium dihydrate.

5. A method according to any one of claims 1 to 4 wherein the mean particle size of the powder is between 1 and 100 μm and the compaction force is sufficiently low that 75% or less by weight of the powder is compacted into acceptable granules having particle size larger than 150μm and/or a mean size of 100μm or greater and the rest remains as fine particles and/or small granules.

6. A method according to any one of claims 1 to 5 wherein the compaction force is 6OkN or less.

7. A method according to claim 6 wherein the compaction force is 45kN or less.

8. A method according to any one of claims 1 to 7 wherein the compaction force is 16kN or more.

9. A method according to any one of claims 1 to 8 wherein the compaction force is applied to the powder by a process comprising use of a roller compactor to generate a ribbon of compacted powder which is broken up to produce granules.

10. A method according to any one of claims 1 to 9 wherein the direction of the flow of the gas stream has a component which is contrary to that of the direction of flow of the compacted mass.

11. A method according to claim 10 wherein the direction of the flow of the gas stream is substantially contrary to that of the direction of flow of the compacted mass.

12.A method according to any one of claims 1 to 11 , characterized in that said compacted mass is moved in said gas stream by effect of gravitation and/or by mechanical means.

13.A method according to any one of claims 1 to 12 wherein the fine particles are separated from the granules by means of an apparatus comprising fractionating means.

14.A method according to claim 13 wherein the fractionating means comprises a fractionating chamber.

15.A method according to claim 13 or claim 14 wherein the fractionating means comprises a rotating device, such as a cylinder or cone, along the axis of which the compacted mass is moved in said gas stream.

16.A method according to claim 15 in which movement of the compacted mass along the axis of the rotating device is guided by means of a spiral structure.

17.A method according to any one of claims 13 to 16 wherein the fractionating means contains apertures through which the fine particles and/or small granules are entrained.

18.A method according to claim 17 for producing granules of mean desired size x wherein the apertures have a minimum dimension of 0.5x.

19.A method according to claim 17 or 18 wherein the apertures have a minimum dimension of 250μm.

20. A method according to any one of claims 13 to 19 wherein the fractionating means does not require passage of the compacted mass through any sieve.

21.A method according to any one of claims 13 to 20 wherein the residence time of the compacted mass within the fractionating means is at least 2 seconds.

22.A method according to any one of claims 1 to 21 , characterized in that said powder comprises an excipient usable in pharmaceutical products and/or a further active pharmaceutical ingredient.

23.A method according to any one of claims 1 to 22 wherein the entrained fine particles and/or small granules are re-circulated for compaction.

24.A method according to any one of claims 1 to 23 wherein the powder is conveyed from a reservoir and/or from the fractionating means to the means to apply the compaction force by means comprising use of a pneumatic conveyor.

25.A method according to any one of claims 1 to 24 further comprising the step of collecting the granules.

26.A method according to claim 25 which is run as a continuous process.

27.A dry-granulated granulate mass containing granules obtainable according to the method of any one of claim 25 or 26.

28.A dry-granulated granulate mass characterized in that the granules comprise at least 60% of ibuprofen sodium dihydrate.

29.A dry-granulated granulate mass according to claim 28 characterized in that the granules comprise at least 80% eg at least 90% eg at least 95% w/w of ibuprofen sodium dihydrate.

30. A dry-granulated granulate mass characterized in that the granules comprise

100% of ibuprofen sodium dihydrate.

31. A granulate mass according to any one of claims 27 to 30, characterized in that said granulate mass has quick dissolution time, good flowability and at least one of the following properties: substantial absence of solid bridges between particles within the granule, good homogeneity, porous structure of the granules, substantial proportion of small granules and/or fine particles in the mass, good compressibility and tabletability.

32.A process for preparing a tablet which comprises compressing a dry- granulated granulate mass according to any one of claims 27 to 31 optionally blended with one or more additional excipients.

33.A process according to claim 32 wherein said one or more additional excipients comprises a lubricant eg in an amount of at least 2% w/w.

34.A process according to claim 33 wherein the lubricant is hydrogenated cottonseed oil.

35.A process according to any one of claims 29 to 34 wherein said one or more additional excipients comprises a disintegrant eg in an amount of 1 -10% w/w.

36.A process according to claim 35 wherein said disintegrant is crospovidone.

37.A process according to any one of claims 29 to 36 wherein said one or more additional excipients comprises a filler eg in an amount of 1 -20% w/w.

38.A process according to claim 37 wherein said filler is microcrystalline cellulose

39.A process according to any one of claims 29 to 38 which comprises compressing a dry-granulated granulate mass comprising 100% ibuprofen sodium dihydrate blended with a lubricant in an amount of 2-5% w/w and optionally one or more disintegrants in an amount of 1 -10% w/w and optionally one or more fillers in an amount of 1 -20%.

40. A tablet obtainable by the process of any one of claims 29 to claim 39.

41. A tablet characterized in that the tablet comprises at least 60% of ibuprofen sodium dihydrate and wherein the balance of the composition is one or more excipients selected from starch and starch derivatives, cellulose and cellulose derivatives and lubricants.

42.A tablet consisting of (a) at least 95% ibuprofen sodium dihydrate (b) 2-5% lubricant.

43.A tablet consisting of (a) at least 80% eg at least 90% eg at least 95% ibuprofen sodium dihydrate (b) 2-5% lubricant and (c) 1 -10% distintegrant.

44.A tablet consisting of (a) at least 80% eg at least 90% eg at least 95% ibuprofen sodium dihydrate (b) 2-5% lubricant (c) 1 -10% distintegrant and (d) 1 -20% filler.

45.A tablet according to any one of claims 41 to 44 wherein the lubricant is hydrogenated cottonseed oil.

46.A tablet according to any one of claims 41 to 45 characterized in that tablet exhibits quick dissolution time and the tablet has at least one eg at least two of the following properties: high tensile strength, high drug load, significant amount of lubricant and substantial absence of solid bridges binding particles within the granules forming the tablet.