Directly compressible mannitol granules

Abstract

The present invention relates to a compressible mannitol granule and a process for its preparation. The present invention also relates to the use of the compressible mannitol granule for the preparation of tablets, in particular by direct compression.

Description

[Technical field]

[0001] The present invention relates to a compressible mannitol granule and a process for its preparation. The present invention also relates to the use of the compressible mannitol granule for the preparation of tablets, in particular by direct compression. [Background technology]

[0002] Direct compression technology allows the rapid and relatively low-cost production of tablets containing precise amounts of active ingredients. This technology consists of forcefully compressing a powdered composition in a die with two punches to give it the shape of a tablet. The high pressure applied causes the powder particles to agglomerate, producing a solid tablet.

[0003] These powdered compositions typically comprise an excipient and an active ingredient of interest, such as an active ingredient of pharmaceutical, veterinary, cosmetic, food, dietary supplement, chemical or pesticide interest.

[0004] The excipients most commonly found in direct compression are diluents (in this case also referred to as "direct compression excipients"), lubricants, (super)disintegrants, flow agents, pH stabilizers, dyes, flavors, surfactants.

[0005] To be able to form a tablet, the powder composition to be compressed always contains at least one direct compression excipient and a lubricant. Direct compression excipients are the majority of the compounds in the tablet and are responsible for the tableting ability and flow properties of the powder. The most commonly used excipients are microcrystalline cellulose and lactose. The lubricant allows the newly formed tablet to be ejected from the die. In some tablet presses, the lubricant is not mixed with the other powders, but is sprayed directly onto the walls to be lubricated. This limits the stress caused by the ejection, thus allowing the integrity of the tablet to be preserved. The most commonly used lubricant is magnesium stearate, followed by calcium stearate and sodium stearyl fumarate.

[0006] A direct compression excipient should ensure that the tablet has sufficient hardness to guarantee its integrity over time, especially during handling, storage and transportation. This hardness can be increased by increasing the compression force applied to the powder being compressed. The higher the compression force (Fc), the denser and harder the resulting tablet will be. However, when using mannitol powder as a direct compression excipient, there is a limit to the use of high compression force to produce tablets of high hardness, a threshold Fc above which tablet stacking occurs. Stacking (including capping and flaking) takes the form of horizontal fracture of the tablet, either in the middle or at the beginning of one of the two dome-shaped parts.

[0007] On the market of direct compression mannitol, PARTECK® M200 (MERCK) is currently the most difficult to obtain. However, as explained above, the stacking phenomenon appears when the Fc applied to PARTECK® M200 is increased, and as a result, a certain hardness cannot be achieved. It would be advantageous to have a mannitol powder that can be used to obtain even harder tablets. This would make it possible, for example, to increase the amount of non-compressible material in the tablet formulation. It would also be advantageous to have a mannitol powder that does not stack easily, in order to give greater freedom in terms of the compression parameters used, in particular to avoid a pre-compression step that is impossible to carry out if the compression press is not equipped. The insensitivity to stacking also makes it possible to eliminate the cylindrical shape and develop dome-shaped tablets that are easy to swallow, especially for patients undergoing long-term treatment, or tablets with shapes that are attractive in the pediatric and dietary supplement fields (sun, star, etc.). This also accelerates the output of the tablet press and therefore the productivity.

[0008] Subject of the Invention It is therefore an object of the present invention to provide a mannitol powder with improved compression behavior, especially under compression conditions compatible with industrial tablet production.

[0009] A particular object of the present invention is to provide a mannitol powder that can be used to prepare tablets with high hardness and / or that does not easily layer.

[0010] The present invention aims to solve the above mentioned problems by proposing a mannitol excipient which additionally possesses other properties required for a direct compression excipient, e.g. in terms of particle size, flow or dissolution.

[0011] Presentation of the invention The present inventors have succeeded in developing mannitol granules that have unique compression behavior.

[0012] These microcrystalline mannitol granules are - the mannitol has a crystalline β content of 90% or more, the microcrystalline mannitol granules have a volume average diameter D(4;3) of ≧90 μm and ≦400 μm, - the microcrystalline mannitol granules have an air permeability density of 600 g / L or more; -Microcrystalline mannitol granules, 0.50m 2 / g or more.

[0013] As can be seen from the following examples, at compression speeds compatible with industrial tablet production, these mannitol granules do not layer even when subjected to extreme compression forces (Fc) of 25 kN, whereas PARTECK® M200 and PEARLITOL® SD layer after 10 kN.

[0014] Thus, it was possible to obtain tablets with a hardness of about 250N using the mannitol granules of the present disclosure, whereas with PARTECK® M200 the maximum hardness was 168N (see FIG. 6). In fact, PARTECK® M200 offers excellent compressibility up to about 10 kN Fc, but nevertheless layers at higher Fc. Finally, the mannitol granules of the present disclosure offer the highest hardness due to their resistance at high Fc.

[0015] The mannitol granules according to the present disclosure have a volume average diameter D(4;3) suitable for use in direct compression of 60-400 μm. The inventors have even succeeded in obtaining granules in the range of 100-200 μm, making them particularly suitable for most pharmaceutical applications. In fact, to ensure a homogeneous mixture of mannitol with any active ingredient present, it is recommended that the mannitol and the active ingredient have the same particle size. However, most pharmaceutical active ingredients have a particle size of 100-200 μm.

[0016] The mannitol granules according to the present disclosure have a lower static charge, good flow properties and low friability, preferably no friability, than those obtained with PEARLITOL® 200SD (Examples, section B), making them excellent candidates for use as container fillers, for example for capsules, sachets and logs (logs are single-dose sachets with a longitudinal, usually tubular shape, commonly referred to as "stick packs"), or for use in continuous processes requiring continuous powder mixing and dosing steps. In addition, the mannitol granules according to the present disclosure have a pleasant slightly sweet taste and a good dissolution profile. These qualities are particularly sought after for use in sachets or logs, where the ingested powder is in direct contact with the oral cavity.

[0017] Mannitol granules according to the present disclosure can be used as a compression excipient in standard tablets as well as in other tablets, such as orally disintegrating tablets, typically in combination with at least one (super)disintegrant (Examples, section C).

[0018] The mannitol granules according to the present disclosure also have very interesting properties for use as a filler in wet or dry granulation (Examples, section D).

[0019] These mannitol granules can be obtained by a continuous process of spray granulation in a fluidized air bed of a mannitol solution, - The granulator bed temperature is 30°C or more and 70°C or less; -Part of the mannitol is recycled.

[0020] This process gives the particles good mechanical strength, its manufacturability is good and there is little variation in the final properties compared to other processes, especially those carried out in batch mode.

[0021] In addition to obtaining mannitol granules with improved compressibility, the process of the present invention can produce powders with low fines content (see FIG. 4B). One hypothesis is that this provides the added advantage that the mannitol granules behave consistently from batch to batch. Although the percentage of fines is perceived as low when expressed by weight, the actual amount of fines is quite different when expressed by number. However, these fines can cause many problems in compression, namely lack of flow, non-homogeneity, lubrication difficulties, press clogging and static electricity. Thus, poor control of the fines content or its variation can adversely affect the compression behavior of mannitol powder.

[0022] Therefore, a further advantage of the process of the present invention is the possibility of reducing these fines.In fact, simple sieving does not improve this problem, as mannitol has self-adhesive properties, especially due to electrostatics, and clogs the sieve very quickly.Moreover, these fines are not effectively removed, since a large amount of fines remain attached to larger particles during sieving.Therefore, instead of removing them, their formation can be avoided in the process of the present invention, while ensuring a satisfactory average size for the final product. Summary of the Invention

[0023] The present invention therefore has as its first object a microcrystalline mannitol granule, - the mannitol has a β-crystal content of 90% or more, the microcrystalline mannitol granules have a volume average diameter D(4;3) of ≧90 μm and ≦400 μm, - the microcrystalline mannitol granules have an air permeability density of 600 g / L or more; -Microcrystalline mannitol granules, 0.50m 2 The microcrystalline mannitol granules are characterized by having a specific surface area of ​​1 / g or more.

[0024] Preferably, the mannitol granules have a crystalline β content of 95% or more.

[0025] Preferably, the mannitol granules have an aerated density of 610 g / L or more.

[0026] Preferably, the mannitol granules have a packing density of 650 g / L or more.

[0027] Preferably, the mannitol granules have a viscosity of 0.60 ml. 2 / g or more.

[0028] The present invention also relates to a powder composition comprising mannitol granules according to the present disclosure and at least one other ingredient.

[0029] The present invention also relates to a process for preparing tablets comprising direct compression of a powdered composition according to the present disclosure.

[0030] A subject of the present invention is also a tablet consisting of the powdery composition according to the present disclosure or obtainable or obtained by the process for preparing tablets according to the present invention.

[0031] Another object of the present invention is the use of the mannitol granules according to the present disclosure as a direct compression excipient, as a filler for filling capsules, sachets or logs and / or as a filler in powder compaction, e.g. by wet or dry granulation.

[0032] The present invention also relates to a process for granulating mannitol, which is a continuous process for granulation by spraying a solution of mannitol into a fluidized air bed, - The granulator fluid bed temperature is 30°C or more and 70°C or less; - a process for granulating mannitol, characterized in that a part of the mannitol is recycled.

[0033] Preferably, in the process, the recycle rate is between 30 and 70% by weight of the product extracted from the granulator, which is preferably even more than 35% by weight of the product extracted from the granulator.

[0034] Preferably, in the process, the recycled mannitol particles have a volume-average diameter D(4;3) of ≧20 μm and ≦150 μm, preferably even greater than 25 μm.

[0035] Preferably, in the process, the mannitol solution to be sprayed has a dry matter content of not less than 20% and not more than 50% by weight. [Brief description of the drawings]

[0036] Other features, details and advantages of the invention will appear from reading the following detailed description and from examining the accompanying drawings. [Figure 1] 1 shows an exemplary diagram of a process according to the present invention. [Diagram 2] 1 is a table showing the properties of mannitol powder according to the present invention and a comparative mannitol powder. [Figure 3A] 3A, 3B, and 3C are scanning electron micrographs of mannitol powders according to the invention and comparative mannitol powders (3D and 3E). [Figure 3B] 3A, 3B, and 3C are scanning electron micrographs of mannitol powders according to the invention and comparative mannitol powders (3D and 3E). [Figure 3C] 3A, 3B, and 3C are scanning electron micrographs of mannitol powders according to the invention and comparative mannitol powders (3D and 3E). [Figure 3D]3A, 3B, and 3C are scanning electron micrographs of mannitol powders according to the invention and comparative mannitol powders (3D and 3E). [Figure 3E] 3A, 3B, and 3C are scanning electron micrographs of mannitol powders according to the invention and comparative mannitol powders (3D and 3E). [Figure 4A] FIG. 4: Particle size distribution by number of a mannitol powder according to the invention (4B) and a comparative mannitol powder (4A). [Figure 4B] FIG. 4: Particle size distribution by number of a mannitol powder according to the invention (4B) and a comparative mannitol powder (4A). [Diagram 5] FIG. 2 shows the compression curve of a mannitol powder according to the invention obtained on a KORSCH XP1 single punch press. [Figure 6] Compression curves for mannitol powder according to the invention and for comparative mannitol powders are shown, tablets were prepared in a single punch development press simulating compression in an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM) at a speed of 25 tablets / min. [Figure 7] Compression curves for mannitol powder according to the invention and for comparative mannitol powders are shown, tablets were prepared in a single punch development press simulating compression in an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM) at a speed of 40 tablets / min. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Mannitol Granules The present invention is, first, a microcrystalline mannitol granule, comprising: - the mannitol has a β-crystal content of 90% or more, the microcrystalline mannitol granules have a volume average diameter D(4;3) of ≧90 μm and ≦400 μm, - the microcrystalline mannitol granules have an air permeability density of 600 g / L or more; -Microcrystalline mannitol granules, 0.50m2 The present invention relates to microcrystalline mannitol granules, characterized by having a specific surface area of ​​1 / g or more.

[0038] The expression "mannitol granules" generally refers to mannitol particles that have an irregular surface, are variable in shape and appear specifically non-spherical when viewed under an electron microscope, for example at 100x magnification.

[0039] At 3000x magnification, fine particles of fine agglomerated crystals are generally visible on the surface of mannitol granules according to the present disclosure.

[0040] Preferably, the mannitol granules according to the present disclosure have a raspberry-like appearance (see, for example, Figures 3A, 3B and 3C, especially at 200x magnification). In contrast, the PEARLITOL® 200SD particles shown in Figure 3D also qualify as mannitol granules, but do not have this raspberry shape and have a smoother surface than the mannitol granules according to the present disclosure.

[0041] Preferably, mannitol granules according to the present disclosure exhibit little porosity, for example at 3000x magnification.

[0042] The expression "microcrystalline" typically refers to a structure that has substantially microcrystals on its surface and few larger crystals when observed under an electron microscope, for example at a magnification of 3000 times. According to the present disclosure, microcrystals can be defined as crystals whose length, width and thickness are less than 25 μm in total. The microcrystals can have very different shapes, from round to elongated. The granules according to the present disclosure preferably have a microstructure that is "non-fibrous". In other words, the length-to-width ratio of the crystallites present on the surface of the granules of the present disclosure is preferably lower than that observed for filaments. In fact, even if needle-shaped crystals may be present, they are present in very small amounts at the surface of the granules according to the present disclosure. By comparison, US Pat. No. 6,998,481 (B2) presents a photograph of a granule with a so-called fibrous structure, since only needle-shaped crystallites are visible. Finally, the crystallites of the mannitol granules according to the present disclosure are generally non-oriented.

[0043] Under an electron microscope and at a magnification of 3000 times, the mannitol granules according to the present disclosure are typically polyhedral, have a regular surface, have a substantially constant thickness but variable length and width, and are easily distinguished from conventional crystalline powders of mannitol, which are generally composed of well-individualized macrocrystals obtained by simple crystallization in water from a solution supersaturated with mannitol. They are further distinguished from mannitol powders obtained by aggregation of a powder composed of mannitol macrocrystals. These granules are not microcrystalline in structure, and the crystals, although no longer in individualized form, are still clearly visible and visible as sharp edges in these granules (examples of such granules are GRANUTOL™ F and S, photographs of which can be found in the paper by ATSUSHI Kosufi et al. "Characterization of Powder-and Tablet Properties of Different Direct Compaction Grades of Mannitol Using a Kohonen Self-organizing Map and a Lasso Regression Model". Journal of Pharmaceutical Sciences xxx(2020)1-9)). For example, it is noted that the process described in the Examples section below uses a mannitol powder (PEARLITOL® 160C) that is composed of macrocrystals. However, this powder is only used in very small amounts and as an initial primer at the very beginning of the process. Therefore, this macrocrystalline structure is not visible in the mannitol granules according to the present disclosure.

[0044] The mannitol granules according to the present disclosure are also distinct from mannitol powders obtained by single-effect spray drying (without a fluidized bed) of mannitol solutions, whose particles, although composed of microcrystalline mannitol, have a very smooth surface, are in the form of a sphere or "deformed sphere", and are generally small in size between 10 and 50 μm (see, for example, Eva M. Littringer et al. "The morphology and various densities of spray dried mannitol". Powder Technology 246 (2013) 193-200, in particular Fig. 1 p. 196). They are further differentiated from mannitol powders obtained by melt / extrusion, which are composed of particles that are more compact and regular, in the form of more or less angular blocks, and consist of roughly oriented crystallites.

[0045] Mannitol granules according to the present disclosure can typically be obtained by a spray granulation process, with process mannitol granules being formed from a mannitol solution. Thus, alternatively or additionally, microcrystalline mannitol granules according to the present disclosure can be defined by the fact that they are granulated or obtained or can be obtained by spray granulation, in particular by a fluidized bed spray granulation process. Also, alternatively or additionally, mannitol granules according to the present disclosure can be defined by the fact that they are not obtained by single effect atomization and / or by melt / extrusion and / or by agglomeration of a powder, in particular composed of macrocrystals, and / or by dry granulation.

[0046] The mannitol granules according to the present disclosure are also characterized by the fact that mannitol comprises at least 90% of the β-crystalline form. The crystalline polymorphism (crystal form and proportion) of mannitol can be determined by the skilled artisan using infrared spectroscopy or X-ray powder diffraction, preferentially X-ray powder diffraction. It is possible to do this, for example, by carrying out the method disclosed in the Examples section below. Preferably, the mannitol granules according to the present disclosure comprise at least 95%, more preferably even at least 97%, more preferably even at least 98%, more preferably even at least 99%, more preferably even 100% of the β-crystalline form. It is noted that these percentages of the β-crystalline form are typically expressed based on the sum represented by the α, β and δ crystalline forms.

[0047] The mannitol granules according to the present disclosure are also characterized by the fact that they have a volume-average diameter D(4;3) of 90 μm or more and 400 μm or less. This volume-average diameter D(4;3) is preferably 100 μm or more, preferably 120 μm or more, preferably 140 μm or more, preferably 150 μm or more, preferably 160 μm or more, preferably 170 μm or more, preferably 180 μm or more, or even 190 μm or more. It is preferably 350 μm or less, preferably 300 μm or less, preferably 250 μm or less, preferably 240 μm or less, preferably less than 230 μm, preferably 220 μm or less, preferably 210 μm or less, or even 200 μm or less. For example, about 190 μm or about 200 μm. This volume-average diameter D(4;3) can be determined by the skilled person, in particular by using a dry laser diffraction particle size analyzer, for example according to the method disclosed in the Examples section below.

[0048] Preferably, the mannitol granules according to the present disclosure have a number D10 of 20 μm or more, preferably 30 μm or more, preferably 40 μm or more, preferably 50 μm or more, preferably 60 μm or more, generally 150 μm or less, or even 120 μm or less, or even 100 μm or less, or even 80 μm or less, or even 70 μm or less.

[0049] Preferably, the mannitol granules according to the present disclosure have a number D50 of 30 μm or more, preferably 50 μm or more, preferably 70 μm or more, preferably 80 μm or more, preferably 90 μm or more, generally 200 μm or less, or even 150 μm or less, or even 140 μm or less, or even 130 μm or less, or even 120 μm or less, or even 110 μm or less, or even 100 μm or less.

[0050] Preferably, the mannitol granules according to the present disclosure have a number D90 of 80 μm or more, preferably 100 μm or more, preferably 110 μm or more, preferably 120 μm or more, preferably 130 μm or more, preferably 140 μm or more, preferably 150 μm or more, generally 300 μm or less, or even 250 μm or less, or even 200 μm or less, or even 190 μm or less, or even 180 μm or less, or even 170 μm or less, or even 160 μm or less.

[0051] Preferably, the mannitol granules according to the present disclosure have a volume D10 of 50 μm or more, preferably 60 μm or more, preferably 70 μm or more, preferably 80 μm or more, generally 200 μm or less, or even 150 μm or less, or even 120 μm or less, or even 110 μm or less, or even 100 μm or less.

[0052] Preferably, the mannitol granules according to the present disclosure have a volume D50 of 100 μm or more, preferably 120 μm or more, preferably 140 μm or more, preferably 150 μm or more, generally 250 μm or less, or even 200 μm or less, or even 180 μm or less, or even 170 μm or less.

[0053] Preferably, the mannitol granules according to the present disclosure have a volume D90 of 200 μm or more, preferably 250 μm or more, preferably 260 μm or more, preferably 280 μm or more, preferably 300 μm or more, preferably 310 μm or more, preferably 320 μm or more, preferably 330 μm or more, generally 450 μm or less, or even 400 μm or less, or even 380 μm or less, or even 370 μm or less, or even 360 μm or less.

[0054] Recall that the D10, D50 and D90 values ​​are the sizes at which 10%, 50% and 90% of the particles have a smaller particle size, respectively. The D10, D50 and D90 values ​​by volume are the sizes at which 10%, 50% and 90% of the particles have a smaller particle size, respectively.

[0055] The D10, D50 and D90 numerical or volumetric values ​​can be determined by the skilled artisan, in particular by using a dry laser diffraction particle size analyzer, for example according to the methods disclosed in the Examples section below.

[0056] The mannitol granules according to the invention are also characterized by the fact that they have an aeration density of 600 g / L or more. Preferably, this aeration density is 610 g / L or more, preferably 620 g / L or more. Generally, it is 750 g / L or less, or even 700 g / L or less, or even 650 g / L or less, or even 640 g / L or less. For example, about 630 g / L or about 620 g / L.

[0057] Preferentially, the mannitol granules according to the present disclosure also have a packing density of 650 g / L or more, preferably 700 g / L or more, preferably 720 g / L or more, preferably 730 g / L or more, preferably 740 g / L or more. In general, it is 850 g / L or less, or even 800 g / L or less, or even 790 g / L or less, or even 780 g / L or less, or even 770 g / L or less, or even 760 g / L or less. For example, about 750 g / L or about 760 g / L.

[0058] The aeration density and packing density can be determined by the skilled artisan using the methods recommended by the European Pharmacopoeia, in particular according to Method 1: "measurement in a graduated cylinder" in European Pharmacopoeia 10.0, 2.9.34.

[0059] The mannitol granules according to the present disclosure have a diameter of 0.50 ml. 2 / g or more, preferably 0.60m 2 / g or more, preferably 0.70m 2 / g or more, preferably 0.75m 2 / g or more, preferably 0.80m 2 / g or more, preferably 0.90m 2 / g or more, preferably 1.00m 2 / g or more, preferably 1.10m 2 / g or more, preferably 1.20m 2 / g or more, preferably 1.30m 2 / g or more. This specific surface area is generally 3.00 m 2 / g or less, or even 2.50m 2 / g or less, or even 2.00m 2 / g or less. For example, about 1.30m 2 / g or about 1.40m 2 / g or about 1.50m 2 This specific surface area can be determined by one of skill in the art using the BET method, for example according to the method disclosed in the Examples section below.

[0060] The mannitol granules according to the invention can also be characterized in that they are mannitol for direct compression or "directly compressible" mannitol. The term "direct compression excipient" is also conventionally used. Thus, the mannitol granules according to the present disclosure can be directly compressed, i.e. compressed without prior texturing or physical transformation treatment, such as a prior step of dry or wet granulation. This is understood to mean that the mannitol granules can form tablets of sufficient hardness by direct compression only in the presence of an effective amount of lubricant. This "effective amount" is such that it effectively allows the formation of tablets, i.e. typically without adhesion or binding, and the ejection force of the tablet from the press is less than 1000 Newtons, for example for the production of 10 tablets. This effective amount of lubricant generally does not exceed 3% by weight relative to the total weight of the powder to be compressed. It is recalled that binding occurs when part of the material adheres to the die, and this adhesion remains after the tablet is ejected. The bonding is visible on the tablet, where vertical lines are present and correspond to the places where the product remains attached to the die.

[0061] This ability to form a satisfactory tablet can be determined, for example, by directly compressing a powdered composition consisting of the excipients and lubricant to be tested, e.g., magnesium stearate, to form a convex tablet having a diameter of 10 mm, a radius of curvature of 9 mm, and a weight of 400 mg. The tablets can be formed by a rotary press or by a single punch expanding press that simulates compression on an industrial rotary press, e.g., as used in the Examples section below. The press speed can be set to 25 tablets / min or 40 tablets / min. In MedelPharm's STYLCAM compression simulator, these speeds correspond to production rates of about 150,000 and 250,000 tablets per hour, respectively, on an industrial rotary press.

[0062] The hardness of the resulting tablets is measured using, for example, a hardness tester such as that used in the Examples section below. The hardness (expressed in Newtons (N)) of tablets prepared from excipients tested in the presence of lubricant alone indicates what is commonly referred to as the "tableting ability" of the excipient.

[0063] According to the test referred to in this disclosure as "Test A", the tableting ability of the excipient being tested is determined by preparing convex 400 mg tablets with a diameter of 10 mm and a radius of curvature of 9 mm on a single punch expanding press simulating compression on an industrial rotary press and then measuring the hardness of the tablets.

[0064] According to this test A, using a speed of 25 tablets / min, the mannitol granules of the present disclosure preferably have a maximum tableting capacity (typically up to 25 kN when Fc varies) of 50N or more, preferably 100N or more, preferably 150N or more, preferably 200N or more, preferably 210N or more, preferably 220N or more, preferably 230N or more, or even 240N or more. This maximum tableting capacity is generally 350N or less, or even 300N or less, or even 280N or less, or even 270N or less, or even 260N or less, or even 250N or less.

[0065] Furthermore, according to this test A, at a speed of 40 tablets / min, this maximum tableting capacity is preferably at least 50 N, preferably at least 100 N, preferably at least 150 N, preferably at least 160 N, preferably at least 170 N, preferably at least 180 N, or even at least 190 N. This maximum tableting capacity is generally at most 350 N, or even at most 300 N, or even at most 250 N, or even at most 230 N, or even at most 210 N, or even at most 200 N.

[0066] The mannitol granules according to the present disclosure can also be characterized by the fact that they do not stack with an Fc of more than 11 kN, preferably more than 15 kN, preferably more than 16 kN, preferably more than 20 kN, preferably more than 24 kN, preferably more than 25 kN, the tablets for this stacking evaluation being produced according to the method of tableting capacity described above (400 mg convex tablets with a diameter of 10 mm and a radius of curvature of 9 mm are obtained in a single punch expanding press simulating compression in an industrial rotary press, using a speed of 25 or 40 tablets per minute). Preferably, the mannitol granules according to the present disclosure do not stack at all according to this test. It should be noted that according to this test, forces of more than 25 kN cannot be applied, since they would damage the punch. In fact, concave punches are more fragile due to their thinner edges, and the maximum Fc they can withstand is also lower.

[0067] Preferably, the mannitol granules according to the present disclosure have a flow grade of 3 to 15 seconds, preferably less than 10 seconds, preferably less than 8 seconds. Usually it is more than 5 seconds, or even more than 6 seconds. This flow grade can be determined by the skilled person according to the method recommended by the European Pharmacopoeia, for example the reference method described in "European Pharmacopoeia 7.0, 2.9.16, "Flow", with equipment for Figure 2.9.16.-2".

[0068] Preferably, the mannitol granules according to the present disclosure are not friable. This friability can be determined by the skilled person according to the methods recommended by the European Pharmacopoeia, for example according to the reference method described in European Pharmacopoeia 10.0,04 / 2012:20941 "2.9.41, Friability of Granules and Spheroids". It is possible to do this, for example, by carrying out the method disclosed in the Examples section below.

[0069] Preferably, the mannitol granules according to the present disclosure have a static charge of less than 10.0 nC / g, preferably 8.0 nC / g or less, preferably 7.0 nC / g or less, preferably 6.0 nC / g or less, preferably 5.0 nC / g or less, which can be determined by one skilled in the art, for example using a GRANUCHARGE™ instrument according to the method disclosed in the examples below.

[0070] Although the mannitol granules according to the present disclosure are mannitol, these granules may contain small amounts of other ingredients, provided that they do not contradict the properties required in the present invention. Examples of other ingredients are polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), cellulosic derivatives, binders such as gum acacia, gelatin, starch derivatives (maltodextrin, gum tragacanth, etc.), minerals, carbohydrates such as sugars and sugar alcohols other than mannitol; food additives, dyes, dietary supplements, pharmaceutical, veterinary or cosmetic active ingredients, preservatives, stabilizers. Preferentially, the content of other ingredients in the granules, in particular the content of carbohydrates other than mannitol, is less than 15.0%, preferentially less than 10.0%, preferentially less than 5.0%, preferentially less than 2.0%, preferentially less than 1.0% and even more preferentially less than 0.5%, these percentages being expressed by weight relative to the total weight of the granule.

[0071] Most preferentially, the mannitol granules according to the present disclosure are free of other components. In the latter case, this means that the granules consist only of mannitol and residual impurities. In these respects, it should be noted that the mannitol according to the present disclosure has a mannitol, especially D-mannitol, richness of preferentially more than 95.0% by dry weight, preferentially more than 96.0%, preferentially more than 97.0%, preferentially more than 97.5%, preferentially more than 98.0%, preferentially more than 98.5%, and most preferentially more than 99.0%, the remainder being residual impurities typically resulting from the production of mannitol. The impurities typically include substances related to mannitol, especially sorbitol, maltitol and isomalt, reducing sugars, nickel, heavy metals. Their content can be determined by the skilled person, for example according to the methods recommended by the European Pharmacopoeia (for example the methods described in the reference "Mannitol, 01 / 2014:0559").

[0072] Preferably, the mannitol granules according to the present disclosure have a mass loss on drying of 0.00 to 0.50% by weight. This mass loss on drying is preferentially 0.40% by weight or less, preferentially 0.30% by weight or less. Generally 0.05% or more, or even 0.10% or more, or even 0.15% or more, or even 0.20% or more. This mass loss on drying can be determined by the skilled person, for example, using the "Karl Fischer" method well known to those skilled in the art.

[0073] Fluidized Air Bed Spray Granulation Process Another object of the present invention is a mannitol granulation process particularly useful for the production of mannitol granules as disclosed above, which is a continuous process for granulation by spraying a solution of mannitol into a fluidized air bed, -The temperature of the granulator fluidized bed is 30°C or more and 70°C or less; - A mannitol granulation process, characterized in that a part of the mannitol is recycled.

[0074] The present granulation process is a spray granulation process. Unlike the "agglomeration" process, in spray granulation the material to be granulated is in liquid form (not powder), in this case in the form of a mannitol solution. The granulated particles are obtained by drying this solution on a primer obtained by recycling a fraction of the granulated particles obtained previously.

[0075] This is also a continuous process. Traditionally, this means that the end product is continuously collected as long as the system is supplied with mannitol solution.

[0076] Preferably, the process according to the present disclosure does not include "exogenous" mannitol powder, i.e., other than that produced by the mannitol solution, except for a negligible amount of mannitol powder that may be used at the beginning of the process for initial priming.

[0077] The temperature of the fluidized bed is 30° C. or more and 70° C. or less. It is preferably 40° C. or more, more preferably 45° C. or more. It is preferably 60° C. or less, more preferably 55° C. or less. For example, about 47° C. or about 51° C.

[0078] The fluidizing air flow rate is typically selected to have a linear velocity in the bed of from 1.0 to 2.0 m / s, preferably about 1.5 m / s.

[0079] The fluidization air temperature is typically set to control the fluidized bed temperature, for example, at or above 100°C and at or below 150°C, for example, at or above 110°C or even at or above 120°C, for example, at or below 140°C, for example, about 130°C.

[0080] Preferably, a circular fluidized bed is used.

[0081] Preferably, the mannitol solution to be sprayed has a dry matter content of 20% by weight or more, preferably 30% by weight or more, preferably 35% by weight or more. It is preferably 50% or less, preferably 45% or less, preferably 40° C. or less. For example, it is selected in the range of about 38 to about 40%.

[0082] Preferably, the mannitol solution to be sprayed is maintained at a temperature that keeps the mannitol in solution (the "feed temperature"). Preferably, this feed temperature is greater than or equal to 70°C, preferably greater than or equal to 75°C, preferably greater than or equal to 80°C, preferably greater than or equal to 85°C. Preferably, it is less than or equal to 100°C, preferably less than or equal to 95°C, preferably less than or equal to 90°C. For example, equal to about 88°C.

[0083] Preferably, the spraying is carried out using two-fluid spray nozzles, the number of which is usually adapted to the size of the fluidized bed. These nozzles can be located either at the top ("top spray") or at the bottom ("bottom spray") of the fluidized bed.

[0084] Preferably, the solution feed rate is 1 / m of fluidized bed. 2 per 1 m of fluidized bed 2 The fluidized bed is preferably 1 m 2 More preferably, 310 kg / h or more per cubic meter of fluidized bed 2 Preferably, the fluidized bed is 1 m 2 380 kg / h or less per fluidized bed, preferably 1 m 2 350 kg / h or less per fluidized bed, more preferably 1 m 2 For example, the fluidized bed is 1 m 2 This is equivalent to approximately 330 kg / h.

[0085] Preferably, the atomization pressure is ≧1.0 bar and ≦4.0 bar. Preferably, it is ≧1.5 bar, preferably ≧2.0 bar, preferably ≧2.5 bar. Preferably, it is ≦3.5 bar, more preferably ≦3.0 bar.

[0086] Preferably, the atomizing air temperature is greater than or equal to 20° C. and less than or equal to 100° C. Preferably less than or equal to 80° C., preferably less than or equal to 60° C., preferably less than or equal to 50° C., preferably less than or equal to 40° C., preferably less than or equal to 30° C. For example, equal to about 25° C.

[0087] The process is a continuous process with recycle so that a fraction of the mannitol granules is continuously extracted from the granulator.

[0088] Preferably, particles having a size of 50 μm or more, preferably 80 μm or more, more preferably about 100 μm or more are extracted, it being understood that smaller particles will still be extracted, unless the means used for this extraction (e.g. classifier) ​​make it possible to obtain a generally clean cut.

[0089] Preferably, this extraction is performed by an air classifier discharge pipe. The particle size threshold for classification is set by the classification air flow rate. Preferably, the classification air flow rate is selected so that the linear velocity in the pipe is between 2.0 and 5.0 m / s, preferably between 3.0 and 4.5 m / s, preferably between 3.3 and 3.8 m / s.

[0090] Preferably, the process according to the invention comprises a step for cooling the mannitol granules after extraction from the granulator, which step is preferably carried out using a vibrating fluidized air bed.

[0091] The process according to the invention involves recycling the granulated mannitol particles, in particular the fines. It is understood that the recycled fraction is reintroduced in dry form, i.e. the granulated mannitol particles are not redissolved in a solution, but are reinjected directly into the granulator bed. The recycled particles typically originate from the mannitol extracted from the granulator. They are recycled as is or after grinding. A small amount of fines transported with the exiting air stream can also be reintroduced into the recycling system, generally in very small amounts compared to particles originating from mannitol extracted, for example, using a classifier.

[0092] Preferably, the mannitol extracted from the granulator is subjected to a separation step for particles considered too fine and / or a separation step for particles considered too coarse, preferably both. Thus, typically, particles considered too fine are fed to a recycling system without the need for grinding. Particles considered too coarse are fed to a recycling system after grinding. Preferably, this separation is carried out after a cooling step, in particular as disclosed above.

[0093] Preferably, when the system is operating continuously and steadily, the recycle rate is 30-70% by weight of the product extracted from the granulator. Preferably, this recycle rate is 35% or more, preferably 40% or more. Preferably, it is 65% or less, preferably 60% or less, preferably 55% or less.

[0094] Preferably, the average diameter of the recycled mannitol particles is smaller than the average diameter of the final desired particles. The volume-average diameter D(4;3) of the recycled mannitol particles is preferably greater than 20 μm and less than 150 μm. Preferably greater than 25 μm, preferably greater than 50 μm, preferably greater than 75 μm, preferably greater than 80 μm. Preferably less than 150 μm, preferably less than 140 μm, preferably less than 130 μm, preferably less than 120 μm.

[0095] Preferably, this separation is achieved by one or more sieves. Preferably, the cut-off threshold used for particles considered to be too fine is ≧50 μm and ≦150 μm. Preferably, it is ≧80 μm, more preferably ≧90 μm. Preferably, it is ≦130 μm, more preferably ≦110 μm. This cut-off threshold is, for example, about 100 μm. The passing fraction is typically and preferably introduced as is (without being crushed) into the recycling system. Preferably, the cut-off threshold used for particles considered to be too coarse is ≧400 μm and ≦800 μm. Preferably, it is ≧450 μm. Preferably, it is ≦700 μm, preferably ≦600 μm, preferably ≦550 μm. This cut-off threshold is, for example, about 500 μm. The retained fraction is typically and preferably introduced into the recycling system after crushing.

[0096] Preferably, these sieving operations are performed in succession. Preferably, the sieves are arranged from highest cut-off to lowest cut-off. Thus, preferably, a sieving to separate particles considered to be too coarse is performed before a sieving to separate particles considered to be too fine.

[0097] The mannitol remaining after separation of particles deemed too coarse and particles deemed too fine can be recovered and conditioned.

[0098] Preferably, an air mill with an integrated classifier is used for grinding, the settings of which (air flow rate, plate speed, classifier / selector speed) make it possible to obtain a fine powder size that ensures system balance. The size of the ground particles is typically smaller than the desired final particle size. Preferably, the volume-average diameter D(4;3) of the ground particles is as defined above for the recycled fraction.

[0099] Preferably, the process includes an initial priming step to allow granulation to begin. For this step, powdered mannitol is introduced into the fluidized bed. Typically, half to the entire bed is filled with this mannitol powder. Preferably, the amount of mannitol is about 1000g per m 3 of the fluidized bed. 2 The amount of mannitol used for the initial priming is preferably 10% or less of the weight of the mannitol granules produced, tending towards 0% after several days of continuous production. In the following examples, crystallized mannitol powder (composed of mannitol macrocrystals) is used for the initial priming. However, it is also possible to use textured mannitol, e.g., atomized or granulated mannitol.

[0100] If the mannitol granules according to the invention comprise other ingredients than mannitol, the granulation process according to the present disclosure includes the use of these other ingredients, which can be introduced into the granulator chamber in dry form, e.g. via a recycle system or additional inlets, and / or in the form of a suspension and / or solution, e.g. via a sprayed mannitol solution. In a preferred embodiment, the granulation process comprises: i1) preparing a mannitol solution; i2) spraying the mannitol solution into a fluid bed granulator until mannitol particles are obtained, the temperature of the fluid bed being ≧30° C. and ≦70° C.; i3) optionally cooling the mannitol particles from step i2), preferably in a fluidized air bed; i4) sieving the mannitol particles from step i2) or step i3), Mannitol granules having a volume average diameter D(4;3) of ≧90 μm and ≦400 μm, optionally - mannitol particles having a diameter of less than 130 μm, preferably less than 110 μm, preferably less than 100 μm (particles which may also be called "fines"), and / or - obtaining mannitol particles (which may also be called "waste") having a diameter of more than 400 μm, preferably more than 450 μm, preferably more than 500 μm; i5) recycling the fines from step i4) to the fluid bed granulator of step i2); and i6) grinding the waste materials from step i4) and recycling them to the granulator from step i2). Preferably, the mannitol granules of step i4) are in accordance with the mannitol granules of the present disclosure.

[0101] Preferably, the recycling rate is as defined above, in particular 30-70% by weight of the mannitol particles from step i2) are recycled according to steps i5) and i6).

[0102] Preferably, at least 35% by weight of the mannitol particles obtained from step i2) are recycled according to steps i5) and i6).

[0103] Preferably, the process also includes an initial priming step i0) in which the bed of the fluidized air granulator is supplied with mannitol powder at the start of the process. Typically, the bed is half to completely filled with this mannitol powder.

[0104] Preferably, the volume-average diameter D(4;3) of the recycled mannitol particles (including fines and milled waste) is as defined above, in particular greater than 25 μm.

[0105] powder composition The subject of the present invention is also a powdery composition, in particular a powdery composition for direct compression, comprising mannitol granules according to the present disclosure and at least one other ingredient.The subject of the present invention is also a powdery composition, in particular a powdery composition for direct compression, comprising mannitol granules obtained or obtainable according to the granulation process according to the present invention and at least one other ingredient.

[0106] This powder composition preferentially comprises: -30.0 to 99.9% mannitol granules according to the present disclosure; -0.1 to 70.0% of components other than the mannitol granules according to the present disclosure, The percentages are expressed by weight and their total equals 100%.

[0107] Examples of other ingredients are typically as follows: - direct compression excipients or diluents other than the mannitol of the present invention, for example (i) directly compressible sugar alcohols such as sorbitol, maltitol, xylitol, isomalt, lactitol, erythritol or mannitol other than that according to the present invention in directly compressible form, (ii) directly compressible sugars such as sucrose, dextrose, dextrates, lactose, allulose in directly compressible form, (iii) microcrystalline cellulose, (iv) directly compressible minerals; - lubricants; dispersants or disintegrants, such as sodium starch glycolate, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone (PVP), starch; - granulating agents such as polyvinylpyrrolidone, cellulose derivatives, gum acacia, dextrose, gelatin, maltodextrin, starch, starch derivatives, gum tragacanth; - food additives, e.g. flavourings, acidifiers; dyes, such as inorganic dyes, pigments or soluble dyes; flow agents (e.g. silicon dioxide) or anti-adherents (e.g. talc); - Active ingredients, in particular pharmaceutical, veterinary, nutraceutical or cosmetic active ingredients.

[0108] Disintegrants are excipients whose role is to facilitate the disintegration of tablets, thus dispersing the active ingredient in water, digestive fluids, or in the oral cavity in the case of orally disintegrating tablets. They ensure the rapid availability of the active ingredient while providing satisfactory rheological properties. The so-called "superdisintegrants" are disintegrants that can be used at even lower concentrations than natural starch. Examples of superdisintegrants include sodium starch glycolate, cross-linked carboxymethylcellulose, and cross-linked PVP.

[0109] Preferentially, the powdered composition according to the present disclosure has a content of mannitol granules according to the invention of less than 20%, preferably less than 30%, preferably less than 40%, this percentage expressed by weight relative to the total weight of the powdered composition, this content of mannitol granules being generally less than 99%, or even less than 90%, or even less than 80%, or even less than 70%.

[0110] Generally, the disclosed powdered compositions have a lubricant content of 0.1-3.0%, preferably 0.2-3.0%, preferably 0.5-3.0%, preferably 1.0-3.0%, preferably 1.0-2.0%, these percentages being expressed by weight relative to the total weight of the powdered composition.

[0111] In an advantageous embodiment, particularly in the case of compositions for the preparation of orally disintegrating tablets, the powdered compositions disclosed comprise a disintegrant, preferably a superdisintegrant.

[0112] The powdered compositions disclosed herein can be used to manufacture tablets. They can also be filler compositions, such as capsule and / or sachet and / or log filler compositions.

[0113] They may be compositions designed for compaction by wet or dry granulation, for example dry granulation by slugging or roller compaction.

[0114] Tablet preparation The present invention also relates to a process for preparing tablets comprising direct compression of the powdered composition according to the present disclosure, preferentially using a rotary press.

[0115] tablet A subject of the present invention is also a tablet consisting of a powdery composition according to the invention or obtainable or obtained by a process for preparing tablets by direct compression according to the invention.

[0116] Conventionally, "tablet" is intended in this disclosure to mean a solid preparation obtained by direct compression of a powdered composition. Tablets may be for example for food, pharmaceutical, cosmetic, nutraceutical use. They may be tablets for sucking, chewing, swallowing, orally disintegrating tablets or effervescent tablets. These tablets may be intended for human, adult or pediatric use, or for animals. They may be tablets for chemical or agrochemical use. These tablets may be single-layer or multi-layer tablets. In this disclosure, tablets preferentially have a curved shape, in other words a convex shape.

[0117] Preferably, the tablet according to the invention has a hardness of 50N or more, preferably 75N or more, preferably 100N or more, preferably 150N or more, preferably 200N or more, preferably 210N or more, preferably 220N or more, preferably 230N or more, or even 240N or more, or even 250N or more, or even 300N or more, or even 350N or more. This hardness is generally 450N or less, or even 400N or less.

[0118] In an advantageous embodiment, the tablet is for use by individuals who have difficulty swallowing and / or for use by children and / or the elderly and / or for use by individuals suffering from swallowing disorders.

[0119] Use of mannitol granules Another object of the present invention is the use of mannitol granules according to the present disclosure as a direct compression excipient, as a filler for filling capsules, sachets or logs and / or as a filler in powder compaction, e.g. by wet or dry granulation.

[0120] Another object of the present invention is the use of mannitol granules according to the present disclosure for the preparation of tablets and / or for filling capsules, sachets or logs and / or in continuous processes, e.g. involving continuous powder mixing and / or dosing, e.g. in a continuous tablet, capsule, log or sachet preparation process, and / or in a powder compaction process, e.g. by wet or dry granulation, e.g. by slugging or roller compaction. Preferably, the granules according to the present disclosure are used as a filler.

[0121] Another object of the present invention is the use of mannitol granules obtained or obtainable according to the granulation process according to the present disclosure as a direct compression excipient, as a filler for filling capsules, sachets or logs and / or as a filler in powder compaction, e.g. by wet or dry granulation.

[0122] In this disclosure, the amounts of ingredients are generally expressed as weight percentages. Unless otherwise stated, these weights are the amount of the ingredient as is, in powdered or oily form. The powdered ingredients generally contain a small amount of water (also called % moisture or "mass loss due to dehydration") and some impurities.

[0123] Conversely, in this disclosure, when dry weight is referred to, this refers to anhydrous weight.

[0124] The invention will be better understood with the aid of the following examples, which are intended to be illustrative and non-limiting. EXAMPLES

[0125] A. Preparation of Mannitol Powder Several mannitol granulated powders were prepared by spray granulation in a fluidized air bed.

[0126] The process was carried out as shown in Figure 1. A fluid bed granulator (type AGT, diameter 1700 mm) was fed with a 38% dry matter mannitol solution. At the start of the process, the fluid bed of the granulator was filled with 600 kg of mannitol powder (mannitol crystals with an average diameter of about 120 μm (PEARLITOL® 160C)). The sprayed solution was granulated in a circular fluid bed. Continuous sieving was carried out on a 3-deck ALLGAIER TSM 2000 / 3 tumbler screen equipped with a 100 μm screen and a 500 μm screen with an ultrasonic head. Particles smaller than 100 μm (considered too fine) were directly recycled, whereas particles larger than 500 μm (considered too coarse) were ground in a PAS 500 POITTEMILL type mill and then reintroduced into the granulator chamber via a recycle system. The 100-500 μm cut was continuously collected to obtain the final product.

[0127] The process conditions are shown in Table 1.

[0128] [Table 1]

[0129] The mannitol granules thus obtained were characterized after 48 hours of continuous operation and compared with commercial and / or prior art mannitol.

[0130] B. Characterization of Mannitol Powder 1. Density determination. The air density and packing density of the test excipients were measured according to the European Pharmacopoeia method (European Pharmacopoeia 10.0, 2.9.34, Method 1: measurement in a graduated cylinder).

[0131] 2. Measurement of the specific surface area. The specific surface area of ​​the excipients tested was determined using a specific surface area analyzer (BECKMAN-COULTER, type SA3100) based on nitrogen absorption tests on the surface of the product subjected to analysis, according to the technique described in the paper BET Surface Area by Nitrogen Absorption by S. BRUNAUER et al. (Journal of American Chemical Society, 60, 309, 1938). The BET analysis was carried out at three points.

[0132] 3. Determination of crystal forms. The ratio of crystal forms was determined by X-ray powder diffraction. The crystal forms (alpha, beta and delta) of mannitol were determined and quantified using an X-ray powder diffraction spectrometer equipped with a copper anode tube (wavelength: 1.54 Å). The analysis was performed successively at 5-60° in reflection using a rotating sample holder. The samples were compressed by hand and deposited as a flat layer on the sample holder. The crystal forms of mannitol were determined by comparing the positions of the diffraction lines of the samples with the corresponding references for the alpha, beta and delta forms of mannitol in the Mannitol Database (alpha reference CSD1142501, beta reference CSD1142500, delta reference CSD662815). Quantitative analysis was performed using the Rietveld method with Topas V6 software (for Bruker spectrometers) using a fundamental parameter approach from the structure files available on the COD (Crystallography Open Database) and CSD (Cambridge Structural Database) databases. The proportion of alpha, beta and delta polymorphs was determined after refining various crystallographic parameters by simulating the diffractogram based on the cif file of the reference product.

[0133] 4. Particle size distribution: Mean diameter D(4;3) and particle size distribution (by number or volume). The mean diameter D(4;3), D10, D50 and D90 (by number or volume) of mannitol powders were measured by dry laser diffraction applying the Fraunhofer theory. The measurements were carried out using a MASTERSIZER 3000 (MALVERN) dry process equipment (the dispersion accessory was Aero S) according to the manufacturer's technical manual and specifications. The dispersion attachment had a modular hopper with an opening of 0-4 mm. The work was carried out with zero pressure, 75% vibration and a hopper opening of 1.5 mm. The measurement range was 0.1 μm to 3500 μm. Obscuration was targeted at 8% to 10%. Two measurements were carried out for each sample. The results are the average of the two measurements. The collected volumetric data were as follows: D(4;3) = mean diameter; D10, D50 and D90. Data recorded in number mode were the same diameters (except for D(4;3), which is always by volume).

[0134] 5. Determination of Flow Grade The flow grade of the tested excipients was determined according to the method recommended by the European Pharmacopoeia (European Pharmacopoeia 7.0, 2.9.16, Flow; apparatus according to Figure 2.9.16.-2).

[0135] The results obtained are shown in the table of FIG. 2, as well as in FIG. 3 (microscopy) and FIG. 4 (number size distribution).

[0136] In a second step, the following parameters were measured on a new batch of mannitol granules according to the present disclosure (MG4) obtained using the process according to the present disclosure:

[0137] 6. Electrostatic charge. Electrostatic charge was measured using GRANUCHARGE™. The GRANUCHARGE™ instrument automatically and accurately measures the amount of electrostatic charge developed inside a powder when it flows in contact with a selected material. The powder sample flows inside a vibrating V-tube and falls into a Faraday cup connected to an electrometer. The electrometer measures the charge acquired by the powder as it flows through the V-tube. For each experiment carried out with GranuCharge, the following method was used: The free-flowing nature of the powder allowed a simple rotation of a beaker to feed it into the stainless steel tube circuit. The amount of powder used to perform the measurements could vary between 20 and 50 g. No recycling can be performed after the measurements. Three different [temperature / humidity] couples were selected to evaluate their influence on the resulting electrostatic charge. To avoid any dependence on temperature, we used absolute humidity as a reference value (water (g) divided by the amount of dry air (kg)).

[0138] The absolute humidity values ​​chosen were: 5.3 g HO / kg dry air (relative humidity (RH) = 35% and temperature (T) = 21 °C. 6.0 g H2O / kg dry air (RH=28% and T=26°C). 7.2g H2O / kg dry air (RH=46% and T=21°C).

[0139] All measurements were repeated four times to assess reproducibility.

[0140] The values ​​obtained were 4.7 nC / g for MG4 mannitol granules and 6.5 nC / g for PEARLITOL® 200SD.

[0141] 7. Friability. Friability was measured using a friability tester (Friabimat SA-400, COPLEY) according to a method adopted from European Pharmacopoeia 10.0, 2.9.41 "Friability of Granules and Spheroids". Triplicate tests were performed (10 g sample per test). Operating conditions were as follows: 400 oscillations / min for 240 seconds. The volumetric particle size distribution of the powder before and after passing through the friability tester was measured according to the method described in item 4. Two measurements were made per sample. No air pressure was applied to avoid breakage. The particle size curves before and after passing through the friability tester were superimposable. In other words, the granules according to the present disclosure are not friable.

[0142] 8. Dissolution time. The dissolution time of the test excipients was determined by measuring the time required to dissolve 5 g of powder immersed in 150 mL of demineralized water at 20 °C using a magnetic stirrer rotating at 200 rpm. 45 mm bar. 250 mL tall beaker. The dissolution time obtained for MG4 Mannitol Granules was 30 seconds.

[0143] C. Direct Compression Test MG1, MG2 and MG3 mannitol granules were first tested for their compression behavior in a KORSCH XP1 single punch press. Extreme compression conditions were chosen (convex tablets, compression speed of 60 tablets per minute) to test the resistance of the mannitol granules to layering.

[0144] The following powder composition was prepared: 98.8% by weight of mannitol and 1.2% by weight of magnesium stearate (vegetable magnesium stearate, WIGA PHARMA GMBH) were mixed for 10 minutes in an epicycloid mixer (TURBULA T2C, Willy A. Bachofen AG Maschinenfabrik, CH-4005 Basel) set at approximately 49 revolutions per minute.

[0145] The powder was compressed with increasing compression force to form convex tablets with a diameter of 10 mm, a radius of curvature of 9 mm and a weight of 400 mg.

[0146] The hardness of the tablets was measured using a hardness tester (PHARMATRON DT 50 503.0064).

[0147] The results are shown in Figure 5.

[0148] Despite the extreme compression conditions, no lamination was observed. Hardnesses of over 300 N and even higher, over 350 N, were obtained. It is also noteworthy that the three batches have similar compression behavior: the process according to the invention is robust and reproducible, producing comparable powders from one batch to the next.

[0149] The mannitol granules were then tested for their compression behaviour using a single punch expanding press which simulates compression in an industrial rotary press and compared to commercial and / or prior art mannitol powders.

[0150] Tablets were prepared in the same manner as in the previous study, except for the press used.

[0151] The press used was a single punch spreading press simulating compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM) controlled by the ANALIS software, using the STYLCAM® standard profile. This press advantageously makes it possible to simulate the operation of an industrial rotary press. Two series of tests were carried out. In the first test, the press was set at a speed of 25 tablets / min. In the second test, the press was set at a speed of 40 tablets / min. This latter speed corresponds to an industrial production rate of 250,000 tablets per hour.

[0152] The hardness of the tablets was measured using a hardness tester (PHARMATRON DT 50 503.0064).

[0153] The results are shown in Figures 6 and 7.

[0154] At the two speeds tested, the mannitol granules according to the present disclosure did not stack, whereas PARTECK® M200 and PEARLITOL® 200 SD stacked after 10-11 kN. Thus, the highest hardness, up to about 250 N (at an Fc of 16 kN), can be achieved with the mannitol granules as disclosed.

[0155] Complementary compression tests were performed on tablets containing the active pharmaceutical ingredient (results not shown here) and the same trends were observed: ie, mannitol granules according to the present disclosure did not layer.

[0156] In this way, the disclosed mannitol granules allow the production of high hardness tablets at high production rates compatible with industrial tablet production. Their resistance to stacking allows the amount of non-compressible ingredients (typically active ingredients) in the tablet to be increased and / or the tablet size to be reduced. This is particularly advantageous for improving treatment compliance, especially in people with swallowing difficulties, such as children, the elderly and / or individuals suffering from dysphagia.

[0157] The disintegration time of tablets prepared at a rate of 25 tablets per minute was evaluated using a method according to European Pharmacopoeia 7.1, 04 / 2011:20901, "2.9.1. Disaggregation of tablets and capsules". The disintegration time averaged 407 seconds (with a minimum of 398 seconds and a maximum of 418 seconds), well below the generally accepted limit of 15 minutes for a standard "immediate release" tablet.

[0158] The mannitol granules according to the present disclosure have the necessary qualities for a compression excipient intended for the industrial production of tablets. They allow the exact filling of the dies, i.e. uniform and reproducible filling with the exact amount of powder, and flow accurately in the equipment used in direct compression. They are chemically and physically stable. They are sufficiently cohesive to allow them to be transported or to allow the preparation of mixtures. They do not interfere with the bioavailability of the other components of the powder, making it possible to obtain tablets that dissolve properly, especially in contact with water. They allow a uniform mixing of the components of the composition and have a good absorption capacity. They allow the formulation of tablets with an acceptable texture and taste required when the tablets are intended to be ingested. They generate packaging and transportation costs in accordance with commercial standards, i.e. there is a good ratio between the weight of the powder to be transported and the volume necessary to package that weight.

[0159] The mannitol granules according to the present disclosure were then used for the preparation of orally disintegrating tablets.

[0160] The following powder composition was prepared: 90.3% by weight of mannitol granules, 0.5% by weight of melatonin (active ingredient), 8% by weight of crospovidone (crosslinked PVP) (KOLLIDON® CL) and 1.2% by weight of magnesium stearate (vegetable magnesium stearate, WIGA PHARMA GMBH). The mannitol granules, melatonin and crospovidone were mixed for 5 minutes in an epicycloid mixer (TURBULA T2C, Willy A. Bachofen AG Maschinenfabrik, CH-4005 Basel) set at approximately 49 rotations per minute (rpm). The magnesium stearate was then added and the mixture was stirred for an additional 5 minutes.

[0161] The powder was pressed to produce beveled tablets of 10 mm diameter (BEVEL EDGE D10 upper and lower punches ref. 2010060-5-1, die ref. 2010060-1) weighing approximately 380 mg and having a hardness of approximately 75 N. A precompression of 10% was applied.

[0162] The press used was a single punch spreader press simulating compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM) controlled by ANALIS software using the KORSCH XL 400 standard profile. The press was set at a speed of 20 tablets per minute, corresponding to an industrial production rate of 71,400 tablets per hour.

[0163] The disintegration rate of the resulting tablets was evaluated in vitro and in vivo.

[0164] The biodisintegration time of the tablets was evaluated using the method according to European Pharmacopoeia 7.1,04 / 2011:20901, "2.9.1. Disaggregation of tablets and capsules".

[0165] When no pre-compression force was applied, the dissolution times obtained were 30 seconds in vivo and 10 seconds in vitro. When a pre-compression force of 1.45 kN was applied, the dissolution times were 35 seconds in vivo and 10 seconds in vitro. These dissolution times are excellent for an orally disintegrating tablet.

[0166] Thus, the mannitol granules according to the present disclosure can be used as a compression excipient in standard tablets as well as other tablets, e.g. orally disintegrating tablets, especially when used in combination with at least one disintegrant, preferably a (super)disintegrant.

[0167] D. Use of the Granules According to the Present Disclosure in Other Applications The mannitol granules according to the present disclosure have a lower static charge, good flowability and are less friable (section B) than those obtained with PEARLITOL® 200SD, making them excellent candidates for use as container fillers, for example for capsules, sachets and logs, or for use in continuous processes requiring continuous powder mixing and dosing steps. In addition, the mannitol granules according to the present disclosure have a pleasant slightly sweet taste and a good dissolution profile. These qualities are particularly desired for use in sachets or logs where the ingested powder is in direct contact with the oral cavity. The mannitol granules according to the present disclosure are also suitable for use in wet or dry granulation.

[0168] To verify the potential of the granules according to the invention in these applications, the following tests were carried out.

[0169] 1.Use for capsule filling Mannitol granules according to the present disclosure were tested as a filler for capsule filling. The powder composition used as filler consisted of 15% by weight of active ingredient (propanolol), 64% by weight of mannitol granules, 20% by weight of partially gelatinized starch (LYCATAB® C, ROQUETTE) and 1% by weight of magnesium stearate. The composition was prepared as follows: the active ingredient, mannitol granules and LYCATAB® C were sieved at 1 mm, then mixed at 40 rpm for 10 minutes (T2F, TURBULA), sieved at 355 μm, then magnesium stearate was added and mixed at 40 rpm for 1 minute. The parameters used for capsule filling were as follows: FlexaLAB MG2 machine (MG AMERICA), powder bed thickness 25 mm, dosing chamber fill height 13.5 mm, compression setting 1 mm, production speed 1000 capsules / hour, capsule size: size 1 (Capsugel®, Lonza), fill weight 270 mg, sampling interval 10 min. Capsule weight and disintegration time were measured at each sampling. Capsule disintegration time was determined in a disintegration tester (PTZ AUTO 3, Pharma Test) in demineralized water at 37°C.

[0170] The capsule weight remained constant over time (350.38±1.30 mg) and the disintegration time was also constant (5.88±1.11 min). These results confirm that the mannitol granules according to the present disclosure are suitable for use as a filler in capsule filling.

[0171] 2. Use in wet granulation The mannitol granules were then tested for use in wet granulation (high shear granulation). The powder composition to be granulated was as follows: 15% by weight propanolol (active ingredient), 62% by weight mannitol granules, 3% by weight pregelatinized cornstarch (LYCATAB® PGS, ROQUETTE), 20% by weight extra white cornstarch. For the granulation, 20% water was used, the percentage being expressed as the weight of water relative to the weight of the powder composition. The granulation was carried out as follows: - Dry mixing in a high shear granulator (Diosna): 300 g of powdered composition sieved to 710 μm, mixing paddle speed 250 rpm, for 180 seconds. - Water added to the granulator: Schlick spray nozzle, 60g water, flow rate approximately 20g / min, for 3 minutes, mixing paddle speed 500 rpm, grinding speed 1800 rpm. -Granulation: mixing paddle speed 500 rpm, grinding speed 1800 rpm, 3 minutes. - Wet grinding in a conical mill (Quadro® Comil®): calibration grid 6350 μm, mesh type: square, rotor type: square, rotation speed 1000 rpm. - Drying in a hot air oven: 60°C overnight. - Dry grinding in a conical mill (Quadro® Comil®): calibration grid 1016 μm, mesh type: file, rotor type: square, rotation speed 1000 rpm.

[0172] The resulting granulated product was measured for particle size (method according to section B.4.), packing density, air density and moisture content.

[0173] The granulated product had a uniform particle size, with a volume D50 of about 200 μm. In contrast, the powder composition before granulation had a bimodal distribution. The air density was 680 g / L, and the packed density was 780 g / L. The Carr index and Hausner index calculated from the density values ​​were 12.59 and 1.14, respectively, indicating good flowability of the obtained granulated product. These results indicate that the granules according to the present disclosure are suitable for use as a filler in wet granulation.

[0174] 3. Use in dry granulation The mannitol granules were then tested for use in dry granulation ("slugging"). The powder composition to be granulated was as follows: 15% by weight propanolol (active ingredient), 54% by weight mannitol granules, 30% by weight microcrystalline cellulose (MICROCEL® 102SD, ROQUETTE), 1% by weight magnesium stearate. The composition was prepared as follows: After passing through a 710 μm sieve, the propanolol, mannitol granules and microcrystalline cellulose were mixed for 10 minutes at 40 rpm (T2F, TURBULA), after passing through a 355 μm sieve, magnesium stearate was added and mixed for 1 minute at 40 rpm. The powder composition was then compressed using the following parameters: STYL'One Evolution press (MEDELPHARM), punch and die: round, chamfered EU-B, 16 mm (Natoli), press speed 25 rpm (Fette P2090 Euro B 54000 tablets / h), compression force about 17 kN, tablet weight 1 g. The hardness of the obtained tablets was measured using a durometer (ST50, SOTAX) and was about 115 N. The obtained tablets were crushed. The dry crushing parameters were as follows: calibration grid 1016 μm, mesh type: file, rotor type: square, rotation speed 3000 rpm.

[0175] The obtained granulated product was measured for particle size (method according to section B.4), packing density and air density. The granulated product had a relatively uniform particle size, with a volume D50 of about 130 μm. The air density was 610 g / L and the packing density was 780 g / L. The Carr index and Hausner index calculated from the density values ​​were 21.97 and 1.28, respectively, indicating a passable flowability of the obtained granulated product. These results show that the disclosed granules are suitable for use as fillers in dry granulation, although process parameters can be optimized in this case as well.

Claims

1. 1. A microcrystalline mannitol granule comprising: the mannitol has a β-crystal content of 90% or more, the microcrystalline mannitol granules have a volume-average diameter D(4;3) of ≧90 μm and ≦400 μm, the microcrystalline mannitol granules have an aerated density of 600 g / L or more, - the microcrystalline mannitol granules have a diameter of 0.50 mm ２ 1. A microcrystalline mannitol granule, characterized in that it has a specific surface area of ​​100 / g or more.

2. 2. Microcrystalline mannitol granules according to claim 1, characterized in that they have a β-crystal content of 95% or more.

3. 3. The microcrystalline mannitol granule according to claim 1 or 2, characterized in that it has an air permeability density of 610 g / L or more.

4. 3. Microcrystalline mannitol granules according to claim 1 or 2, characterized in that they have a packing density of 650 g / L or more.

5. 0.60 m ２ 3. Microcrystalline mannitol granules according to claim 1 or 2, characterized in that they have a specific surface area of ​​more than 100 / g.

6. A powder composition comprising the microcrystalline mannitol granules of claim 1 and at least one other ingredient.

7. 7. A process for preparing a tablet comprising direct compression of the powdered composition of claim 6.

8. 8. A tablet consisting of the powdered composition according to claim 6 or obtainable or obtained by the tablet preparation process according to claim 7.

9. As a direct compression excipient, a filler for filling capsules, sachets or logs; 3. Use of the microcrystalline mannitol granules according to claim 1 or 2 as a filler in powder compaction, for example by wet or dry granulation.

10. A process for granulating mannitol, comprising: a continuous process for granulation by fluidized air bed atomization of a mannitol solution, - the granulator fluid bed temperature is ≧30° C. and ≦70° C. - a process for granulating mannitol, characterized in that a part of said mannitol is recycled.

11. 11. The process for granulating mannitol according to claim 10, characterized in that the recycle rate is between 30 and 70% by weight of the product extracted from the granulator.

12. 12. A process for granulating mannitol according to claim 11, characterized in that the recycling rate is equal to or greater than 35% by weight of the product extracted from the granulator.

13. 13. The process for granulating mannitol according to any one of claims 10 to 12, characterized in that the volume-average diameter D(4;3) of the recycled mannitol particles is ≧20 μm and ≦150 μm.

14. 14. A process for granulating mannitol according to claim 13, characterized in that the volume-average diameter D(4;3) of the recycled mannitol particles is greater than 25 μm.

15. 13. A process for granulating mannitol according to any one of claims 10 to 12, characterized in that the mannitol solution to be sprayed has a dry substance of ≧20% and ≦50% by weight.

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