Directly compressible mannitol granules

Abstract

The invention relates to compressible mannitol granules and to a process for the preparation thereof. The invention also relates to their use for the preparation of tablets, in particular by direct compression.

Description

Description Title: Directly compressible mannitol granules Technical field

[0001] The invention relates to compressible mannitol granules, as well as to a process for their preparation. The invention also relates to their use for the preparation of tablets, in particular by direct compression. Technological background

[0002] Direct compression techniques allow the manufacture of tablets containing precise amounts of active ingredients at high speed and at relatively low cost. This technology involves compressing a powdered composition tightly into a die using two punches, thus forming it into a tablet. The high pressure applied causes the powder particles to clump together, producing a solid tablet.

[0003] These powdered compositions typically comprise excipients and active ingredients of interest, for example pharmaceutical, veterinary, cosmetic, food, nutraceutical, chemical or agrochemical.

[0004] The most commonly encountered excipients in direct compression are diluents, also called "direct compression excipients" in this case, lubricants, (super-)disintegrants, flow agents, pH stabilizing agents, colorants, flavors, surfactants.

[0005] In order to be suitable for forming tablets, the powder composition to be compressed always includes at least one direct compression excipient and one lubricant. Direct compression excipients are the main components of tablets and are responsible for the tableting and flow properties of the powder. The most commonly used are microcrystalline cellulose and lactose. The lubricant allows the ejection of the newly formed tablet dies. On some tablet presses, the lubricant is not mixed with the other powders but sprayed directly onto the walls to be lubricated. It limits the stress induced by ejection and therefore helps preserve the integrity of the tablets. The most commonly used is magnesium stearate, followed by calcium stearate and sodium stearyl fumarate.

[0006] The direct compression excipient should allow the production of tablets of sufficient hardness, in particular to guarantee their integrity over time, and in particular during various handling, storage and transport. This hardness can be increased by increasing the compression force applied to the powder to be compressed. The higher the compression force (Fc), the denser and harder the tablet obtained will be. When using mannitol powder as a direct compression excipient, the use of high compression forces in order to obtain tablets of high hardness has its limits, however: there is in fact a limit Fc from which tablet cleavage phenomena appear. Cleavage (including uncapping and rolling) appears in the form of a horizontal fracturing of the tablets, either in their middle or at the beginning of one of the two domed parts.

[0007] On the market for mannitols for direct compression, PARTECK® M200 (MERCK) currently provides the highest hardnesses. However, as explained above, cleavage phenomena occur when increasing the Fc applied to PARTECK® M200, so that certain hardnesses cannot be achieved. It would be advantageous to have a mannitol powder that allows tablets of even higher hardness to be obtained. This would, for example, make it possible to increase the amount of non-compressible materials in the tablet formulation. It would also be advantageous to have a mannitol powder that does not cleave easily, in order to give more freedom in the compression parameters used, and in particular to avoid the pre-compression step, which is impossible to carry out when the tablet press is not equipped with one.The non-sensitivity to cleavage also makes it possible to move away from the cylindrical shape and develop domed tablets that are easier to swallow - particularly for patients on long-term treatment - or tablets with attractive shapes (such as sun or star) in the pediatric and nutraceutical fields. This also makes it possible to speed up the speed of tablet presses and therefore productivity. Objectives of the invention

[0008] The present invention thus aims to provide a mannitol powder having improved compression behavior, in particular under compression conditions compatible with industrial production of tablets.

[0009] The present invention in particular aims to provide a mannitol powder making it possible to manufacture tablets of high hardness, and / or which do not cleave easily.

[0010] The present invention aims to address the above-mentioned problems by providing a mannitol excipient which also has the other properties required for a direct compression excipient, for example in terms of particle size, flow or dissolution. Presentation of the invention

[0011] The inventors have succeeded in developing mannitol granules that exhibit a completely unique compression behavior.

[0012] These microcrystalline mannitol granules are characterized in that: - mannitol has a crystalline form P content greater than or equal to 90%; - they have an arithmetic mean diameter in volume D(4;3) greater than or equal to 90 pm and less than or equal to 400 pm; - they have an aerated density greater than or equal to 600 g / L; - they have a specific surface area greater than or equal to 0.50 m 2 / g.

[0013] As shown in the examples below, at compression speeds compatible with industrial tablet production, these mannitol granules do not cleave, even when applying extreme compression forces (Fc) of 25 kN. Conversely, PARTECK® M200 and PEARLITOL® SD cleave after 10 kN.

[0014] Thus, it was possible to obtain tablets having a hardness of approximately 250 N with the mannitol granules of the present description, whereas with PARTECK® M200 the maximum hardness was 168 N (see Figure 6). Indeed, even if PARTECK® M200 has a higher compressibility up to approximately 10 kN of Fc, the latter nevertheless cleaves at higher Fc. It is therefore ultimately the mannitol granules of the present description which make it possible to obtain the highest hardnesses, thanks to its resistance to high Fc.

[0015] The mannitol granules according to the present description have an arithmetic mean diameter by volume D(4;3) suitable for use in direct compression of 60 to 400 pm. The inventors have even succeeded in obtaining granules in the range of 100-200 pm, which makes them particularly suitable for most pharmaceutical uses. Indeed, to guarantee the homogeneous mixing of mannitol with any active ingredients 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 pm.

[0016] The mannitol granules according to the present description have a lower electrostatic charge than that obtained with PEARLITOL® 200SD, a good flow and have low friability, preferably are not friable (Examples, section B.), which makes them an excellent candidate for use in filling containers, for example capsules, sachets, and stickpacks (stickpacks are single-dose sachets of longitudinal shape, most often tubular, commonly referred to as "stickpacks"), or for use in continuous processes, which require continuous mixing and dosing steps of powder. In addition, the mannitol granules according to the present description have a pleasant, slightly sweet taste and have a good dissolution profile.These qualities are particularly sought after for use in sachets or sticks, where the powder to be ingested comes into direct contact with the oral cavity.

[0017] The mannitol granules according to the present description can be used as a compression excipient in standard tablets as well as in other tablets, for example in orodispersible tablets, typically in combination with at least one (super-)disintegrant (Examples, section C.).

[0018] The mannitol granules according to the present description 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, in which: - the temperature of the granulator bed is greater than or equal to 30°C and less than or equal to 70°C; and, - a fraction of the mannitol is recycled.

[0020] This process provides very good mechanical resistance of the particles. Its productivity is good, and there is little variability in the final properties compared to other processes, particularly those carried out in batch mode.

[0021] In addition to making it possible to obtain mannitol granules with improved compressibility, the method of the invention can make it possible to obtain powders low in fines (see Figure 4B). One hypothesis is that this makes it possible to obtain an additional advantage which is that the mannitol granules exhibit homogeneous behavior from one batch to another. A percentage of fines expressed by weight will be perceived as low, but the reality of the quantity of fines in number is totally different. However, these fines can generate numerous problems in compression: lack of flow, non-homogeneity, difficulty in lubrication, fouling of the press, static electricity. Poor control of the fines rate or a variation in it can therefore have a negative influence on the compression behavior of the mannitol powder.

[0022] An additional advantage of the process of the invention is therefore to offer the possibility of reducing these fines. Indeed, simple sieving does not solve this problem: mannitol has self-adhesion properties, in particular by static electricity and clogs the sieves very quickly. In addition, since a large quantity of fines remains stuck to the largest particles during sieving, these fines are not effectively eliminated. Thus, instead of eliminating them, their formation can be avoided in the process of the invention; and this, while guaranteeing a satisfactory average size for the finished product. Summary of the invention

[0023] The invention thus has as its first subject microcrystalline mannitol granules, characterized in that: - said mannitol has a content of crystalline form P greater than or equal to 90%; and, - they have an arithmetic mean diameter in volume D(4;3) greater than or equal to 90 pm and less than or equal to 400 pm; and, - they have an aerated density greater than or equal to 600 g / L; and, - they have a specific surface area greater than or equal to 0.50 m 2 / g.

[0024] Preferably, said mannitol granules have a content of crystalline form P greater than or equal to 95%.

[0025] Preferably, said mannitol granules have an aerated density greater than or equal to 610 g / L.

[0026] Preferably, said mannitol granules have a packed density greater than or equal to 650 g / L.

[0027] Preferably, said mannitol granules have a specific surface area greater than or equal to 0.60 m 2 / g.

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

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

[0030] The invention also relates to a tablet composed of the powdery composition according to the present description, or capable of being obtained by, or obtained by the process for preparing tablets according to the invention.

[0031] The invention also relates to the use of the mannitol granules according to the present description, as a direct compression excipient, as a filler for filling capsules, sachets or sticks, and / or as a filler in the shaping of powders, for example by wet or dry granulation.

[0032] The invention also relates to a process for granulating mannitol, characterized in that it is a continuous process for granulation by spraying a mannitol solution in a fluidized air bed, in which: - the temperature of the fluidized bed of the granulator is greater than or equal to 30°C and less than or equal to 70°C; and, - a fraction of the mannitol is recycled.

[0033] Preferably in said process, the recycling rate is 30 to 70% by weight of the product which is extracted from the granulator. It is more preferably greater than or equal to 35% by weight of the product which is extracted from the granulator.

[0034] Preferably in said process, the arithmetic mean diameter in volume D(4;3) of the recycled mannitol particles is greater than or equal to 20 pm and less than or equal to 150 pm. It is more preferably greater than 25 pm.

[0035] Preferably in said method, the sprayed mannitol solution has a dry matter by weight greater than or equal to 20%, and less than or equal to 50%. Brief description of the drawings

[0036] Other characteristics, details and advantages of the invention will appear on reading the detailed description below, and on analyzing the attached drawings, in which: Figure 1

[0037] [Fig. 1] Figure 1 represents an example of a diagram of a method according to the invention. Figure 2

[0038] [Fig. 2] Figure 2 is a characterization table of mannitol powders in accordance with the invention and comparative mannitol powders. Figure 3

[0039] [Fig. 3A] [Fig. 3B] [Fig. 3C] [Fig. 3D] [Fig. 3E] Figures 3A, 3B, 3C, 3D, and 3E are photographs taken using a scanning electron microscope of mannitol powders in accordance with the invention (3A, 3B, 3C) and comparative mannitol powders (3D, 3E). Figure 4

[0040] [Fig. 4A] [Fig. 4B] Figures 4A and 4B are number particle size distributions of mannitol powders according to the invention (4B) and comparative mannitol powders (4A). Figure 5

[0041] [Fig. 5] Figure 5 represents compression curves of mannitol powders in accordance with the invention, obtained on the KORSCH XP1 single-punch press. Figure 6

[0042] [Fig. 6] Figure 6 represents compression curves of mannitol powders in accordance with the invention and of comparative mannitol powders, the tablets having been prepared at a rate of 25 tablets / minute on a single-punch development press which simulates compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM). Figure 7

[0043] [Fig. 7] Figure 7 represents compression curves of mannitol powders in accordance with the invention and of comparative mannitol powders, the tablets having been prepared at a rate of 40 tablets / minute on a single-punch development press which simulates compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM). Detailed description of the invention

[0044] Mannitol granules

[0045] The invention relates firstly to microcrystalline mannitol granules, characterized in that: - said mannitol has a content of crystalline form P greater than or equal to 90%; and, - they have an arithmetic mean diameter in volume D(4;3) greater than or equal to 90 pm and less than or equal to 400 pm; and, - they have an aerated density greater than or equal to 600 g / L; and, - they have a specific surface area greater than or equal to 0.50 m 2 / g.

[0046] The expression "mannitol granules" classically refers to mannitol particles which, when observed under an electron microscope, at a magnification of X100 for example, appear to be of variable shapes, in particular non-spherical, and with an irregular surface.

[0047] At a magnification of X3000, fine particles of fine agglomerated crystals are usually visible on the surface of mannitol granules as described.

[0048] Preferably, the mannitol granules according to the present description have a raspberry appearance (see for example Figures 3A, 3B and 3C, in particular at x200 magnification). In contrast, it is noted that the particles of the PEARLITOL® 200 SD shown in Figure 3D, although they can also be described as mannitol granules, do not have this raspberry shape, and have a smoother surface than the mannitol granules according to the present description.

[0049] Preferably, the mannitol granules according to the present description have little porosity, at a magnification of, for example, X3000.

[0050] The expression "microcrystalline" typically refers to a structure which, observed under an electron microscope at a magnification of, for example, X3000, has on the surface essentially microcrystals and very rarely larger crystals. According to the present description, a microcrystal can be defined as a crystal whose sum of the length, width and thickness is less than 25 μm. The microcrystals can have very different shapes, from rounded shapes to elongated shapes. The granules according to the present description have a microstructure which is preferably "non-filamentous". In other words, the length to width ratio of the microcrystals present on the surface of the granules of the present description is preferably lower than what is observed for filaments.Indeed, even if needle-shaped crystals may be present, these are very much in the minority on the surface of the granules in accordance with the description. In comparison, US patent 6,998,481 B2 shows a photo of a granule with a so-called filamentary texture because only needle-shaped microcrystals are visible. Finally, generally, the microcrystals of the mannitol granules according to the present description are not oriented.

[0051] Under an electron microscope and at a magnification of X3000, the mannitol granules according to the present description are easily differentiated from conventional crystalline mannitol powders, composed of well-individualized, typically polyhedral macrocrystals, with a regular surface, substantially constant thickness but variable length and width, generally obtained by simple crystallization in water, from a supersaturated mannitol solution. They are further differentiated from mannitol powders obtained by agglomeration of a powder composed of mannitol macrocrystals. These granules are not of microcrystalline structure: the crystals, although no longer in individualized form, are still clearly visible and appear in the form of sharp edges in these granules (examples of such granules are GRANUTOL™ F and S, photographs of which can be seen in the article 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). Note that the process described for example in the Example section below uses a mannitol powder (PEARLITOL® 160C) composed of macrocrystals. However, this powder is only used as an initial primer, in very small quantities, and at the very beginning of the process. Thus, this macrocrystalline structure is not visible in the mannitol granules according to the present description.

[0052] The mannitol granules according to the present description also differ from mannitol powders obtained by single-effect spray drying (not using a fluidized bed) of a mannitol solution, the particles of which, although composed of microcrystalline mannitol, have a very smooth surface, are spherical or in the form of “deformed spheres” and of small diameter, generally 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, and in particular, Figure 1 p. 196). They further differ from mannitol powders obtained by melting / extrusion, which are formed of more compact and more regular particles, in the form of more or less angular blocks, and which are made up of generally oriented microcrystals.

[0053] The mannitol granules according to the description may typically be obtained by a spray granulation process, a process in which mannitol granules are formed from a mannitol solution. Thus, alternatively, or additionally, the microcrystalline mannitol granules according to the present description may be defined by the fact that they are granulated, or that they are obtained, or capable of being obtained, by spray granulation, in particular by a fluidized bed spray granulation process. Also, alternatively or additionally, the mannitol granules according to the present description may be defined by the fact that they are not obtained by single-effect atomization, and / or by melting / extrusion, and / or by agglomeration of a powder, in particular composed of macrocrystals, and / or by dry granulation.

[0054] The mannitol granules according to the present description are also characterized by the fact that the mannitol comprises at least 90% of crystalline form p. The crystalline polymorphism of mannitol (crystalline forms and proportions) can be determined by a person skilled in the art by infrared spectrometry or by powder X-ray diffraction, preferably by powder X-ray diffraction. For example, the method as described in the Examples section below can be used. Preferably, the mannitol granules according to the present description comprise at least 95% of crystalline form P, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably 100%. Note that these percentages of crystalline form P are typically expressed as a function of the total represented by the crystalline forms a, P, and 5.

[0055] The mannitol granules according to the present description are also characterized by the fact that they have an arithmetic mean diameter in volume D(4;3) greater than or equal to 90 and less than or equal to 400 pm. This arithmetic mean diameter in volume D(4;3) is preferably greater than or equal to 100 pm, preferably greater than or equal to 120 pm, preferably greater than or equal to 140 pm, preferably greater than or equal to 150 pm, preferably greater than or equal to 160 pm, preferably greater than or equal to 170 pm, preferably greater than or equal to 180 pm, or even greater than or equal to 190 pm. It is preferably less than or equal to 350 pm, preferably less than or equal to 300 pm, preferably less than or equal to 250 pm, preferably less than or equal to 240 pm, preferably less than or equal to 230 pm, preferably less than or equal to 220 pm, preferably less than or equal to 210 pm, or even less than or equal to 200 pm. It is for example equal to approximately 190 pm, or equal to approximately 200 pm. This arithmetic mean diameter in volume D(4;3) can in particular be determined by a person skilled in the art using a dry laser diffraction granulometer, for example according to the method as described in the Examples section below.

[0056] Preferably, the mannitol granules according to the description have a D10 in number greater than or equal to 20 pm, preferably greater than or equal to 30 pm, preferably greater than or equal to 40 pm, preferably greater than or equal to 50 pm, preferably greater than or equal to 60 pm. It is generally less than or equal to 150 pm, or even less than or equal to 120 pm, or even less than or equal to 100 pm, or even less than or equal to 80 pm, or even less than or equal to 70 pm.

[0057] Preferably, the mannitol granules according to the description have a D50 in number greater than or equal to 30 pm, preferably greater than or equal to 50 pm, preferably greater than or equal to 70 pm, preferably greater than or equal to 80 pm, preferably greater than or equal to 90 pm. It is generally less than or equal to 200 pm, or even less than or equal to 150 pm, or even less than or equal to 140 pm, or even less than or equal to 130 pm, or even less than or equal to 120 pm, or even less than or equal to 110 pm, or even less than or equal to 100 pm.

[0058] Preferably, the mannitol granules according to the description have a D90 in number greater than or equal to 80 pm, preferably greater than or equal to 100 pm, preferably greater than or equal to 110 pm, preferably greater than or equal to 120 pm, preferably greater than or equal to 130 pm, preferably greater than or equal to 140 pm, preferably greater than or equal to 150 pm. It is generally less than or equal to 300 pm, or even less than or equal to 250 pm, or even less than or equal to 200 pm, or even less than or equal to 190 pm, or even less than or equal to 180 pm, or even less than or equal to 170 pm, or even less than or equal to 160 pm.

[0059] Preferably, the mannitol granules according to the description have a D10 by volume greater than or equal to 50 pm, preferably greater than or equal to 60 pm, preferably greater than or equal to 70 pm, preferably greater than or equal to 80 pm. It is generally less than or equal to 200 pm, or even less than or equal to 150 pm, or even less than or equal to 120 pm, or even less than or equal to 110 pm, or even less than or equal to 100 pm.

[0060] Preferably, the mannitol granules according to the description have a D50 by volume greater than or equal to 100 pm, preferably greater than or equal to 120 pm, preferably greater than or equal to 140 pm, preferably greater than or equal to 150 pm. It is generally less than or equal to 250 pm, or even less than or equal to 200 pm, or even less than or equal to 180 pm, or even less than or equal to 170 pm.

[0061] Preferably, the mannitol granules according to the description have a D90 by volume greater than or equal to 200 pm, preferably greater than or equal to 250 pm, preferably greater than or equal to 260 pm, preferably greater than or equal to 280 pm, preferably greater than or equal to 300 pm, preferably greater than or equal to 310 pm, preferably greater than or equal to 320 pm, preferably greater than or equal to 330 pm. It is generally less than or equal to 450 pm, or even less than or equal to 400 pm, or even less than or equal to 380 pm, or even less than or equal to 370 pm, or even less than or equal to 360 pm.

[0062] It is recalled that the values ​​of D10, D50 and D90 in number are the sizes for which 10%, 50% and 90% respectively in number of the particles have a smaller particle size. The values ​​of D10, D50 and D90 in volume are the sizes for which 10%, 50% and 90% respectively in volume of the particles have a smaller particle size.

[0063] The values ​​of D10, D50 and D90 in number or in volume can in particular be determined by a person skilled in the art using a dry laser diffraction granulometer, for example according to the method as described in the Examples section below.

[0064] The mannitol granules according to the description are also characterized by the fact that they have an aerated density greater than or equal to 600 g / L. Preferably, this aerated density is greater than or equal to 610 g / L, preferably greater than or equal to 620 g / L. It is generally less than or equal to 750 g / L, or even less than or equal to 700 g / L, or even less than or equal to 650 g / L, or even less than or equal to 640 g / L. It is for example equal to approximately 630 g / L, or equal to approximately 620 g / L.

[0065] Preferably, the mannitol granules according to the present description also have a packed density greater than or equal to 650 g / L, preferably greater than or equal to 700 g / L, preferably greater than or equal to 720 g / L, preferably greater than or equal to 730 g / L, preferably greater than or equal to 740 g / L. It is generally less than or equal to 850 g / L, or even less than or equal to 800 g / L, or even less than or equal to 790 g / L, or even less than or equal to 780 g / L, or even less than or equal to 770 g / L, or even less than or equal to 760 g / L. It is for example equal to approximately 750 g / L, or equal to approximately 760 g / L.

[0066] This aerated density and this packed density can be determined by a person skilled in the art according to the method recommended by the European Pharmacopoeia, in particular in accordance with Method 1: “measurement in a graduated cylinder” described in the European Pharmacopoeia 10.0, 2.9.34.

[0067] Mannitol granules conforming to the description have a specific surface area greater than or equal to 0.50 m 2 / g, preferably greater than or equal to 0.60 m 2 / g, preferably greater than or equal to 0.70 m 2 / g, preferably greater than or equal to 0.75 m 2 / g, preferably greater than or equal to 0.80 m 2 / g, preferably greater than or equal to 0.90 m 2 / g, preferably greater than or equal to 1.00 m 2 / g, preferably greater than or equal to 1.10 m 2 / g, preferably greater than or equal to 1.20 m 2 / g, preferably greater than or equal to 1.30 m 2 / g. This specific surface area is generally less than or equal to 3.00 m 2 / g, or less than or equal to 2.50 m 2 / g, or less than or equal to 2.00 m 2 / g. it is for example equal to approximately 1.30 m 2 / g, or equal to approximately 1.40 m 2 / g, or equal to approximately 1.50 m 2 / g. This specific surface area can be determined by a person skilled in the art by the BET method, for example according to the method as described in the Example section below.

[0068] Mannitol granules according to the description may also be characterized as being mannitol for direct compression or mannitol "directly compressible". This is also conventionally referred to as a "direct compression excipient". The mannitol granules in accordance with the description can thus be compressed directly, i.e. without any prior texturizing or physical transformation treatment, such as, for example, a prior dry or wet granulation step. It is understood that this means that the mannitol granules are capable of forming tablets of sufficient hardness, by direct compression, in the sole presence of an effective quantity of lubricant. This "effective quantity" is such that it effectively allows the formation of tablets, i.e., typically, there is no sticking or seizing, and the ejection force of the tablet from the press is less than 1000 Newtons, for a production run of, for example, 10 tablets. This effective quantity of lubricant generally does not exceed 3% by weight, relative to the total weight of the powder to be compressed.It is recalled that "seizing" corresponds to the sticking of a part of the material on the matrix, sticking which persists after ejection of the tablet. Seizing is visible on the tablet: vertical lines are present and correspond to the places where the product remained stuck on the matrix.

[0069] This ability to form satisfactory tablets may be determined, for example, by direct compression of a powder composition consisting of the excipient to be tested and a lubricant, for example, magnesium stearate, so as to form convex tablets 10 mm in diameter with a radius of curvature of 9 mm and a weight of 400 mg. The tablets may be formed using a rotary press, or using a single-punch developing press which simulates compression on an industrial rotary press, for example, such as that used in the Examples section below. The press speed may be set at 25 tablets per minute or 40 tablets per minute. On MedelPharm's STYLCAM compression simulator, these speeds correspond approximately to production rates of 150,000 and 250,000 tablets per hour on an industrial rotary press, respectively.

[0070] On the tablets thus obtained, hardness measurements are carried out using a durometer, for example such as that used in the Examples section below. The hardness of the tablets prepared from the excipient to be tested in the The sole presence of the lubricant, expressed in Newtons (N), designates what is commonly called the “tableting capacity” of the excipient.

[0071] According to a test designated "test A" in this description, the compressibility of the excipient to be tested is determined as follows: 400 mg tablets, convex, 10 mm in diameter and with a radius of curvature of 9 mm, are prepared on a single-punch development press simulating compression on an industrial rotary press; the hardness of the tablets is then measured.

[0072] According to this test A, using a rate of 25 tablets per minute, the mannitol granules of the present description preferably have a maximum compressibility (when varying the Fc, typically up to 25 kN) greater than or equal to 50 N, preferably greater than or equal to 100 N, preferably greater than or equal to 150 N, preferably greater than or equal to 200 N, preferably greater than or equal to 210 N, preferably greater than or equal to 220 N, preferably greater than or equal to 230 N, or even greater than or equal to 240 N. This maximum compressibility is generally less than or equal to 350 N, or even less than or equal to 300 N, or even less than or equal to 280 N, or even less than or equal to 270 N, or even less than or equal to 260 N, or even less than or equal to 250 N.

[0073] Still according to this test A, at a rate of 40 tablets per minute, this maximum compressibility is preferably greater than or equal to 50 N, preferably greater than or equal to 100 N, preferably greater than or equal to 150 N, preferably greater than or equal to 160 N, preferably greater than or equal to 170 N, preferably greater than or equal to 180 N, or even greater than or equal to 190 N. This maximum compressibility is generally less than or equal to 350 N, or even less than or equal to 300 N, or even less than or equal to 250 N, or even less than or equal to 230 N, or even less than or equal to 210 N, or even less than or equal to 200 N.

[0074] The mannitol granules according to the description may also be characterized by the fact that they do not cleave at an Fc greater than 11 kN, preferably greater than or equal to 15 kN, preferably greater than or equal to 16 kN, preferably greater than or equal to 20 kN, preferably greater than or equal to 24 kN, preferably greater than or equal to 25 kN; the tablets for this cleavage evaluation being made according to the method mentioned above for compressibility (400 mg tablets, convex, 10 mm in diameter and with a radius of curvature of 9 mm, obtained on a single-punch developing press which simulates compression on an industrial rotary press, using a rate of 25 or 40 tablets per minute). Preferably, the mannitol granules of the present description do not cleave at all according to this test. It should be noted that according to this test, it is not possible to compress at forces greater than 25 kN, because there would be a risk of damaging the punch. Indeed, concave-shaped punches are more fragile and withstand lower maximum Fc, because their edge is thinned.

[0075] Preferably, the mannitol granules according to the present description have a flow rate of 3 to 15 seconds, preferably less than or equal to 10 seconds, preferably less than or equal to 8 seconds. It is generally greater than or equal to 5 seconds, or even greater than or equal to 6 seconds. This flow rate can be determined by a person skilled in the art according to the method recommended by the European Pharmacopoeia, for example the reference method described in the “European Pharmacopoeia 7.0, 2.9.16, “Flow”; with equipment according to figure 2.9.16.-2”.

[0076] Preferably, the mannitol granules according to the present description are not friable. This friability can be determined by the person skilled in the art according to the method recommended by the European Pharmacopoeia, for example according to the reference method described in the European Pharmacopoeia 10.0, 04 / 2012:20941 “2.9.41, Friability of Granules and Spheroids”. For example, the method as described in the Examples section below can be used.

[0077] Preferably, the mannitol granules according to the present description have an electrostatic charge of less than 10.0 nC / g, preferably less than or equal to 8.0 nC / g, preferably less than or equal to 7.0 nC / g, preferably less than or equal to 6.0 nC / g, preferably less than or equal to 5.0 nC / g. This electrostatic charge can be determined by the person skilled in the art using the GRANUCHARGE™ instrument, for example according to the method as described in the examples below.

[0078] The mannitol granules of the present description are mannitol, but these granules may however comprise other ingredients, in small quantities, and as long as this does not contravene the properties sought in the present invention. Examples of other ingredients are: binders such as polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), cellulose derivatives, acacia gum, gelatin, starch derivatives such as maltodextrins, tragacanth gum; minerals; carbohydrates such as sugars and sugar alcohols other than mannitol; food additives, colorants; nutraceutical, pharmaceutical, veterinary or cosmetic active ingredients; preservatives; stabilizing agents.Preferably, the content of other ingredients in the granules, in particular the content of carbohydrates other than mannitol, is less than 15.0%, preferably less than 10.0%, preferably less than 5.0%, preferably less than 2.0%, preferably less than 1.0%, preferably still less than 0.5%; these percentages being expressed by weight relative to the total weight of granules.

[0079] Most preferably, the mannitol granules according to the present description are free of other ingredients. In the latter case, this means that the granules consist only of mannitol and residual impurities. Note in this regard that the mannitol according to the present description preferably has a mannitol content, in particular D-mannitol, greater than 95.0% by dry weight, preferably greater than 96.0%, preferably greater than 97.0%, preferably greater than 97.5%, preferably greater than 98.0%, preferably greater than 98.5%, most preferably greater than 99.0%, the remainder being residual impurities typically originating from the manufacture of mannitol. The impurities typically include substances related to mannitol, in particular sorbitol, maltitol and isomalt, reducing sugars, nickel, heavy metals.Their contents can be determined by a person skilled in the art, for example according to the methods recommended by the European Pharmacopoeia (for example the method described in the reference document “Mannitol, 01 / 2014:0559”).

[0080] Preferably, the mannitol granules according to the present description have a loss of mass on drying of 0.00 to 0.50% by weight. This loss of mass on drying is preferably less than or equal to 0.40% by weight, preferably less than or equal to 0.30%. It is generally greater than or equal to 0.05%, or even greater than or equal to 0.10%, or even greater than or equal to 0.15%, or even greater than or equal to 0.20%. This loss of mass on drying can be determined by a person skilled in the art, for example according to the so-called "Karl Fischer" method, well known to a person skilled in the art.

[0081] Fluidized bed spray granulation process

[0082] The present invention also relates to a process for granulating mannitol, particularly useful for the manufacture of the mannitol granules described above, characterized in that it is a continuous process for granulation by spraying in a fluidized air bed of a mannitol solution, in which: - the temperature of the fluidized bed of the granulator is greater than or equal to 30°C and less than or equal to 70°C; and, - a fraction of the mannitol is recycled.

[0083] The granulation process is a spray granulation process. Unlike so-called "agglomeration" processes, in spray granulation, the material to be granulated is in liquid form (and not in powder form), in this case in the form of a mannitol solution. The granulated particles come from drying this solution on a primer obtained by recycling a fraction of the previously obtained granulated particles.

[0084] It is also a continuous process. This typically means that the final product is collected continuously, as long as the system is supplied with mannitol solution.

[0085] Preferably, the method according to the description does not involve "exogenous" mannitol powder, i.e. other than that generated by the mannitol solution; with the exception of negligible quantities of mannitol powder which may be used at the start of the method for initial priming.

[0086] The temperature of the fluidized bed is greater than or equal to 30°C and less than or equal to 70°C. It is preferably greater than or equal to 40°C, more preferably greater than or equal to 45°C. It is preferably less than or equal to 60°C, more preferably less than or equal to 55°C. It is for example approximately equal to 47°C or approximately equal to 51°C.

[0087] The fluidization air flow rate is typically chosen to have a linear velocity in the bed between 1.0 and 2.0 m / s, preferably around 1.5 m / s.

[0088] The fluidization air temperature is typically set to control the fluidized bed temperature. For example, it is greater than or equal to 100°C, and less than or equal to 150°C. For example, it is greater than or equal to 110°C, or even greater than or equal to 120°C. For example, it is less than or equal to 140°C. For example, it is approximately equal to 130°C.

[0089] Preferably, the fluidized bed employed is a circular fluidized bed.

[0090] Preferably, the sprayed mannitol solution has a dry matter by weight greater than or equal to 20%, preferably greater than or equal to 30%, preferably greater than or equal to 35%. It is preferably less than or equal to 50%, preferably less than or equal to 45%, preferably less than or equal to 40°C. It is for example chosen in a range of about 38 to about 40%.

[0091] Preferably, the sprayed mannitol solution is maintained at a temperature ("feed temperature") that allows the mannitol to be kept in solution. 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. It is preferably less than or equal to 100°C, preferably less than or equal to 95°C, preferably less than or equal to 90°C. It is for example approximately equal to 88°C.

[0092] Preferably, spraying is carried out by means of bi-fluid spray nozzle(s). Their number will be conventionally adapted to the size of the fluidized bed. These nozzles can be placed indifferently at the top (“top spray”) or at the bottom (“bottom spray”) of the fluidized bed.

[0093] Preferably, the solution feed rate is greater than or equal to 300 kg / h / m 2 fluidized bed, and less than or equal to 400 kg / h / m 2 fluidized bed. It is preferably greater than or equal to 310 kg / h / m 2 fluidized bed, preferably greater than or equal to 320 kg / h / m 2 fluidized bed. It is preferably less than or equal to 380 kg / h / m 2 fluidized bed, preferably less than or equal to 350 kg / h / m 2 fluidized bed, preferably less than or equal to 340 kg / h / m 2 fluidized bed. For example, it is approximately equal to 330 kg / h / m 2 fluidized bed.

[0094] Preferably, the spray pressure is greater than or equal to 1.0 bar and less than or equal to 4.0 bar. It is preferably greater than or equal to 1.5 bar, preferably greater than or equal to 2.0 bar, preferably greater than or equal to 2.5 bar. It is preferably less than or equal to 3.5 bar, preferably less than or equal to 3.0 bar.

[0095] Preferably, the spray air temperature is greater than or equal to 20°C and less than or equal to 100°C. It is 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. It is for example approximately equal to 25°C.

[0096] Since the process is a continuous process involving recycling, a fraction of mannitol granules is continuously extracted from the granulator.

[0097] Preferably, particles having a size greater than or equal to 50 pm, preferably greater than or equal to 80 pm, preferably greater than or equal to approximately 100 pm are extracted. It is understood that particles of smaller size are still extracted, insofar as the means implemented for this extraction (for example a classifier) ​​generally do not allow a clean cut to be obtained.

[0098] Preferably, this extraction is provided by means of an air classifier discharge tube. The particle size threshold for classification is set by the classification air flow rate. Preferably, the classification air flow rate is chosen so as to have a linear velocity in the tube of between 2.0 and 5.0 m / s, preferably between 3.0 and 4.5 m / s and preferably between 3.3 and 3.8 m / s.

[0099] Preferably, the method according to the description comprises a step of cooling the mannitol granules, after extraction from the granulator. This step is preferably carried out by means of a vibrated fluidized air bed.

[0100] The method according to the description comprises the recycling of granulated mannitol particles, in particular fines. It is understood that the recycled fraction is reintroduced in dry form, that is to say that the granulated mannitol particles are not resolubilized in solution but directly reinjected into the granulator bed. The recycled particles typically come from the mannitol extracted from the granulator. They are recycled as such, or after grinding. The few fine particles transported with the outgoing air flow can also be reintroduced into the recycling system, and are generally in very small quantities compared to the particles coming from the mannitol extracted, for example using the classifier.

[0101] Preferably, the mannitol extracted from the granulator undergoes a step of separating particles considered too fine, and / or a step of separating particles considered too large, preferably both. Thus, typically, particles considered too fine will feed the recycling system without grinding being necessary. Particles considered too large will feed the recycling system after grinding. Preferably, this separation is carried out after a cooling step, in particular as described above.

[0102] Preferably, when the system operates continuously and is in steady state, the recycling rate is 30 to 70% by weight of the product extracted from the granulator. Preferably, this recycling rate is greater than or equal to 35%, preferably greater than or equal to 40%. It is preferably less than or equal to 65%, preferably less than or equal to 60%, preferably less than or equal to 55%.

[0103] Preferably, the average diameter of the recycled mannitol particles is less than the average diameter of the particles ultimately desired. Thus, the arithmetic mean diameter in volume D(4;3) of the recycled mannitol particles is preferably greater than or equal to 20 pm and less than or equal to 150 pm. It is preferably greater than 25 pm, preferably greater than 50 pm, preferably greater than 75 pm, preferably greater than or equal to 80 pm. It is preferably less than or equal to 150 pm, preferably less than or equal to 140 pm, preferably less than or equal to 130 pm, preferably less than or equal to 120 pm.

[0104] Preferably, this separation is ensured by means of one or more sievings. Preferably, the cut-off threshold used for particles considered too fine is greater than or equal to 50 pm and less than or equal to 150 pm. It is preferably greater than or equal to 80 pm, preferably greater than or equal to 90 pm. It is preferably less than or equal to 130 pm, preferably less than or equal to 110 pm. This cut-off threshold is for example equal to approximately 100 pm. The fraction which passes is typically and preferably introduced as is (without undergoing grinding) into the recycling system. Preferably, the cut-off threshold used for particles considered too large is greater than or equal to 400 pm and less than or equal to 800 pm. It is preferably greater than or equal to 450 pm. It is preferably less than or equal to 700 pm, preferably less than or equal to 600 pm, preferably less than or equal to 550 pm.This cut-off threshold is for example equal to approximately 500 pm. The retained fraction is typically and preferably introduced into the recycling system after grinding.

[0105] Preferably, these sievings are carried out in series. Preferably, the sieves are arranged from the highest to the lowest cut-off threshold. Thus, preferably, the sieving aimed at separating particles considered too large is carried out before the sieving aimed at separating particles considered too fine.

[0106] The mannitol remaining after separation of particles considered too large and too fine is collected and can be packaged.

[0107] Preferably for grinding, an air mill with an integrated classifier is used, the settings of which (air flow, plate speed, classifier / selector speed) allow a fines size to be obtained which ensures the balance of the system. The size of the ground particles is typically smaller than the desired final particle size. Preferably, the arithmetic mean diameter in volume D(4;3) of the ground particles is as defined before for the recycled fraction.

[0108] Preferably, the method comprises an initial priming step, in order to allow the granulation to start. For this step, powdered mannitol is introduced into the fluidized bed. The bed will typically be filled between half and the entirety with this mannitol powder. Preferably, this quantity of mannitol is less than or equal to 300 kg / m 2fluidized bed. It should be remembered that this "exogenous" mannitol represents a very small quantity of mannitol compared to the total quantity of mannitol used. For example, 200 to 600 kg of powder will be used to produce 7 tonnes of mannitol granules over 24 hours. Thus, typically, the quantity of mannitol used for initial priming is preferably less than or equal to 10% relative to the weight of mannitol granules produced, and will tend towards 0% after several days of continuous production. In the examples below, a crystallized mannitol powder (composed of mannitol macrocrystals) is used for initial priming. But it is also possible to use textured mannitol, for example atomized or granulated.

[0109] In the event that the mannitol granules according to the description comprise other ingredients than mannitol, the granulation process according to the description includes the use of these other ingredients, which may be introduced in dry form into the granulator chamber, for example via the recycling system or an additional inlet, and / or in the form of a suspension and / or solution, for example via the sprayed mannitol solution. In a preferred embodiment, the granulation method comprises: 11) the preparation of a mannitol solution; 12) spraying the mannitol solution into a fluidized bed granulator, the temperature of the fluidized bed being greater than or equal to 30°C and less than or equal to 70°C until mannitol particles are obtained; 13) optionally, cooling the mannitol particles from step i2) preferably in a fluidized air bed; 14) sieving the mannitol particles from step i2) or step i3) so as to obtain: - mannitol granules having an arithmetic mean diameter by volume D(4;3) greater than or equal to 90 pm and less than or equal to 400 pm, and, optionally: - mannitol particles having a diameter of less than 130 pm, preferably less than 110 pm, preferably less than 100 pm, (particles which can also be referred to as “fines”), and / or - mannitol particles having a diameter greater than 400 pm, preferably greater than 450 pm, preferably greater than 500 pm, (particles which can also be referred to as “refusals”); 15) recycling of the fines from step i4) to the fluidized air bed granulator of step Î2); 16) crushing of the reject from step i4) then its recycling in the granulator from step i2). Preferably, the mannitol granules of step i4) conform to the mannitol granules of the present description.

[0110] Preferably, the recycling rate is as defined above. In particular, 30 to 70% by weight of the mannitol particles from step i2) are recycled according to step i5) and step i6).

[0111] Preferably, at least 35% by weight of the mannitol particles obtained at the end of step i2) are recycled according to step i5) and step i6).

[0112] Preferably, the method also comprises an initial priming step iO), in which the bed of the fluidized air bed granulator is supplied at the start of the process with a mannitol powder. Typically, between half and all of the bed will be filled with this mannitol powder.

[0113] Preferably, the arithmetic mean diameter in volume D(4;3) of the recycled mannitol particles (including fines and crushed residue) is as defined above, in particular is greater than 25 pm.

[0114] Powdery composition

[0115] The present invention also relates to a powder composition, in particular a powder composition for direct compression, comprising the mannitol granules according to the description and at least one other ingredient. The present invention also relates to a powder composition, in particular a powder composition for direct compression, comprising the mannitol granules obtained or capable of being obtained according to the granulation process in accordance with the description, and at least one other ingredient.

[0116] This powdery composition is preferably made up of: - 30.0 to 99.9% of mannitol granules according to the present description; - 0.1 to 70.0% of ingredients other than mannitol granules conforming to the description; the percentages being expressed by weight, and their sum being equal to 100%.

[0117] Examples of other ingredients are typically: - direct compression excipients or diluents other than the mannitol of the invention, for example (i) directly compressible sugar alcohols such as the directly compressible forms of sorbitol, maltitol, xylitol, isomalt, lactitol, erythritol, or mannitol other than that of the invention (ii) directly compressible sugars such as the directly compressible forms of sucrose, dextrose, dextrates, lactose, allulose (iii) microcrystalline cellulose, (iv) directly compressible minerals; - lubricants; - dispersants or disintegrants, such as sodium starch glycolate, crosslinked carboxymethylcellulose, crosslinked polyvinylpyrrolidone (PVP), starches; - granulating agents such as polyvinylpyrrolidone, cellulose derivatives, acacia gum, dextrose, gelatin, maltodextrins, starches, starch derivatives, tragacanth gum; - food additives, such as flavorings, acidifiers; - colorants such as mineral dyes, pigments or soluble dyes; - flow agents (e.g. silica dioxide), or anti-adhesion agents (e.g. talc); - active ingredients, including pharmaceutical, veterinary, nutraceutical, or cosmetic.

[0118] Disintegrants are excipients whose role is to accelerate the disintegration of the tablet, therefore the dispersion of the active ingredient in water, in digestive juices or even in the oral cavity in the case of tablets. orodispersible. It ensures rapid availability of active substances, while exhibiting satisfactory rheological properties. The so-called "super-disintegrants" are disintegrants that can be used at even lower concentrations than that of native starch. Examples of super-disintegrants are sodium starch glycolate, crosslinked carboxymethylcellulose, crosslinked PVP.

[0119] Preferably, the powdery composition in accordance with the description has a content of mannitol granules in accordance with the description greater than or equal to 20%, preferably greater than or equal to 30%, preferably greater than or equal to 40%; these percentages being expressed by weight relative to the total weight of the powdery composition. This content of mannitol granules is generally less than or equal to 99%, or even less than or equal to 90%, or even less than or equal to 80%, or even less than or equal to 70%.

[0120] Generally, the powdery composition according to the description has a lubricant content of 0.1 to 3.0%, preferably 0.2 to 3.0%, preferably 0.5 to 3.0%, preferably 1.0 to 3.0%, preferably 1.0 to 2.0%; these percentages being expressed by weight relative to the total weight of the powdery composition.

[0121] In an advantageous embodiment, in particular if it is a composition for the manufacture of orodispersible tablets, the powdery composition according to the description comprises a disintegrant, preferably a super-disintegrant.

[0122] The powdery compositions according to the description can be used for the manufacture of tablets. They can also be filling compositions (“fillers”), for example compositions for filling capsules, and / or sachets, and / or sticks.

[0123] These may also be compositions intended to be shaped by wet or dry granulation, for example by dry granulation by briquetting (“slugging” in English) or by roller compaction (“roller compaction” in English).

[0124] Preparation of tablets

[0125] The present invention also relates to a process for preparing tablets, comprising the direct compression of a powdery composition according to the present description, preferably by means of a rotary press.

[0126] Tablets

[0127] The present invention also relates to a tablet composed of the powdery composition in accordance with the description, or capable of being obtained by, or obtained by the process for preparing tablets by direct compression in accordance with the description.

[0128] In the present description, the term "tablet" is conventionally understood to mean a solid preparation obtained by direct compression of a powdered composition. The tablet may be, for example, for food, pharmaceutical, cosmetic or nutraceutical use. It may be tablets to be sucked, chewed or swallowed, orally dispersible tablets or effervescent tablets. These tablets may be intended for humans, adults or children, or for animals. It may also be tablets for chemical or agrochemical use. These tablets may be single-layer or multi-layer. In the present description, the tablets are preferably domed or, in other words, convex in shape.

[0129] Preferably, the tablet according to the description has a hardness greater than or equal to 50 N, preferably greater than or equal to 75 N, preferably greater than or equal to 100 N, preferably greater than or equal to 150 N, preferably greater than or equal to 200 N, preferably greater than or equal to 210 N, preferably greater than or equal to 220 N, preferably greater than or equal to 230 N, or even greater than or equal to 240 N, or even greater than or equal to 250 N, or even greater than or equal to 300 N, or even greater than or equal to 350 N. This hardness is generally less than or equal to 450 N, or even less than or equal to 400 N.

[0130] In an advantageous embodiment, the tablets are for use in individuals having difficulty swallowing, and / or for use in children and / or in the elderly, and / or for use in individuals suffering from dysphagia.

[0131] Use of Mannitol Granules

[0132] The present invention also relates to the use of the mannitol granules in accordance with the description as a direct compression excipient, as a filler for filling capsules, sachets or sticks, and / or as a filler in the shaping of powders, for example by wet or dry granulation.

[0133] The present invention also relates to the use of the mannitol granules according to the description for the preparation of tablets, and / or for filling capsules, sachets or sticks, and / or in continuous processes, comprising for example the continuous mixing and / or dosing of powder, for example in a continuous process for the preparation of tablets, capsules, sticks or sachets, and / or in processes for shaping powder, for example by wet or dry granulation, for example by briquetting or by roller compacting. Preferably, the granules according to the description are used as a bulking agent.

[0134] The present invention also relates to the use of mannitol granules obtained or capable of being obtained according to the granulation process in accordance with the description, as a direct compression excipient, as a filler for filling capsules, sachets or sticks, and / or as a filler in the shaping of powders, for example by wet or dry granulation.

[0135] In this description, the amounts of ingredients are generally expressed as percentages by weight. Unless otherwise indicated, these weights are amounts of ingredients as such in their powdered or oily form. Powdered ingredients generally contain small amounts of water (also referred to as % moisture or "loss of mass on drying") and some impurities.

[0136] In contrast, in the present description, when referring to a dry weight, this refers to anhydrous weights.

[0137] The invention will be better understood with the aid of the following examples, which are intended to be illustrative and not limiting. Examples

[0138] A. Preparation of mannitol powders

[0139] Several mannitol granule powders were prepared by fluidized bed spray granulation.

[0140] The process was carried out according to the diagram shown in Figure 1. The granulator equipped with a fluidized bed (AGT type granulator diameter 1700 mm) was fed with a mannitol solution at 38% dry matter. At the start of the process, the fluidized bed of the granulator was filled with 600 kg of mannitol powder (mannitol crystals with an average diameter of approximately 120 μm (PEARLITOL® 160C). The sprayed solution was granulated in a circular fluidized bed. Sieving was carried out continuously on a three-stage ALLGAIER TSM 2000 / 3 nutating sieve equipped with a 100 pm mesh with ultrasonic heads and a 500 pm mesh. Particles smaller than 100 pm (considered too fine) were recycled directly, while particles larger than 500 pm (considered too coarse) were ground on a POITTEMILL PAS 500 type mill and then reintroduced into the granulator chamber via the recycling system. The 100-500 pm cut was collected continuously to obtain the finished product.

[0141] The process conditions are shown in Table 1.

[0142] [Table 1] continuous were characterized and compared to commercial and / or prior art mannitols.

[0144] B. Characterization of mannitol powders

[0145] 1. Determination of densities. The aerated and packed densities of the test excipients were measured according to the method in accordance with the European Pharmacopoeia (European Pharmacopoeia 10.0, 2.9.34, Method 1: measurement in a graduated cylinder).

[0146] 2. Determination of the specific surface area. The specific surfaces of the excipients to be tested were determined using a specific surface area analyzer (BECKMAN-COULTER, type SA3100), based on a nitrogen absorption test on the surface of the product subjected to analysis, following the technique described in the article 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 3 points.

[0147] 3. Determination of crystalline forms. The ratio of crystalline forms was determined by powder X-ray diffraction: the determination of the crystalline forms of mannitol (alpha, beta and delta) as well as their quantifications were carried out using a powder X-ray diffraction spectrometer with a copper anode tube (wavelength: 1.54 Å). The analysis was carried out continuously, from 5 to 60°, in reflection, with a rotating sample holder. The sample was compacted manually and deposited in a flat layer on the sample holder. The crystalline forms of mannitol were determined by comparing the positions of the diffraction lines of the sample with the mannitol databases (Alpha ref CSD1142501; Beta ref CSD1142500; Delta ref CSD 662815), corresponding to the references of the alpha, beta and delta forms of mannitol.Quantitative analysis was performed using the Rietveld method with Topas V6 software (in the case of a Bruker spectrometer), using the fundamental parameter approach from the structure files available on the COD (Crystallography Open Database) and CSD (Cambridge Structural Database) databases. Thus, the determination of the proportions of alpha, beta and delta type polymorphs was performed by simulating a diffractogram from the cif files of the reference products and after refinement of the different crystallographic parameters.

[0148] 4. Granulometry: average diameter D(4;3) and number or size distribution. The average diameter D(4;3), D10, D50 and the D90 (by number or volume) of mannitol powders was measured by dry laser diffraction, applying Fraunhofer theory. The measurement was carried out with MASTERSIZER 3000 equipment (MALVERN) in dry process (dispersion accessory was Aero S), following the technical manual and specifications of the manufacturer. The dispersion accessory had a modular hopper with an opening of 0 to 4 mm. We worked at zero pressure, 75% vibration and a hopper opening of 1.5 mm. The measuring range was from 0.1 pm to 3500 pm. The obscuration was targeted between 8% and 10%. 2 measurements were carried out for each sample. The result is the average of the two measurements. The data recorded in volume were: D(4;3) = arithmetic mean diameter; D10, D50 and D90. The data recorded in number mode were the same diameters (except D(4;3) which is always in volume).

[0149] 5. Determination of the flow rate. The flow rate of the excipients to be tested was measured according to the method recommended by the European Pharmacopoeia (European Pharmacopoeia 7.0, 2.9.16, Flow; equipment according to figure 2.9.16.-2).

[0150] The results obtained are presented in the table shown in Figure 2, as well as in Figure 3 (microscopy) and Figure 4 (number granulometry).

[0151] In a second step, the following parameters were measured on a new batch of mannitol granules conforming to the description (MG4), obtained according to the process conforming to the description.

[0152] 6. Electrostatic charge. Electrostatic charge was measured using the GRANUCHARGE™. The GRANUCHARGE™ instrument automatically and accurately measures the amount of electrostatic charge created inside a powder when flowing 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 during flow inside the V-tube. For each experiment carried out with the GranuCharge, the following method was used: the free-flowing properties of the powder allowed the use of the simple beaker rotation method to feed the stainless steel pipe circuit. The amount of powder used for a measurement can vary between 20-50g. No recycling can be carried out after a measurement.Three different [temperature / humidity] pairs were selected to evaluate their influence on the obtained electrostatic charge. To avoid any temperature dependence, we used absolute humidity as a reference value (Water (in g) divided by the amount of dry air (in kg)).

[0153] The selected absolute humidity values ​​were:

[0154] 5.3g H2O / kg of dry air (Relative Humidity (RH) = 35% and temperature (T°) = 21 °C.

[0155] 6.0g H2O / kg of dry air (RH=28% and T°=26°C)

[0156] 7.2g H2O / kg of dry air (RH=46% and T°=21°C)

[0157] All measurements were repeated 4 times to assess their reproducibility.

[0158] The values ​​obtained were 4.7 nC / g for MG4 mannitol granules, and 6.5 nC / g for PEARLITOL® 200SD.

[0159] 7. Friability. Friability was determined using a friability tester (Friabimat SA-400, COPLEY), according to a method adapted from the European Pharmacopoeia 10.0, 2.9.41 “Friability of Granules and Spheroids”. The tests were conducted in triplicate (10 g of sample per test). The operating conditions were as follows: 400 oscillations per minute, for 240 seconds. The volume particle size distribution of the powder before and after passing through the friability tester was determined according to the method given in point 4. Two measurements per sample were made. No air pressure was applied to avoid breakage. The particle size distribution curves before and after passing through the friability tester were superimposable. In other words, granules conforming to the description are not friable.

[0160] 8. Dissolution time. The dissolution time of the test excipient 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 stir bar. 250 mL tall beaker. The dissolution time obtained for MG4 mannitol granules was 30 seconds.

[0161] C. Direct compression tests

[0162] Mannitol granules MG1, MG2 and MG3 were first tested for their compression behavior on a KORSCH XP1 single-punch press. Extreme compression conditions were chosen to test the mannitol granules' resistance to cleavage (convex tablets, compression speed of 60 tablets per minute).

[0163] The following powder compositions were prepared: 98.8% by weight of mannitol and 1.2% by weight of magnesium stearate (Vegetal magnesium stearate, WIGA PHARMA GMBH) were mixed for 10 minutes in an epicyclic mixer (TURBULA T2C, Willy A. Bachofen AG Maschinenfabrik, CH-4005 Basel), set at approximately 49 rotations per minute.

[0164] The powders were compressed using increasing compression forces to form convex tablets of 10 mm diameter with a radius of curvature of 9 mm, and a weight of 400 mg.

[0165] The hardness of the tablets was measured using a durometer (PHARMATRON DT 50 503.0064).

[0166] The results are shown in Figure 5.

[0167] Despite extreme compression conditions, no cleavage was observed. High hardnesses were obtained, greater than 300 N, or even greater than 350 N. It is also noted that the 3 batches have similar compression behavior: the process according to the invention is robust and reproducible, and produces powders comparable from one batch to another.

[0168] The mannitol granules were then tested for their compression behavior using a single-punch developing press that simulates compression on an industrial rotary press, and compared to commercial and / or prior art mannitol powders.

[0169] The tablets were prepared in the same manner as in the previous trial, except for the press used.

[0170] The press used was a single-punch development press that simulates compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM), controlled using ANALIS software, using the standard STYLCAM® profile. This press advantageously simulates the operation of industrial rotary presses. Two series of tests were carried out: in a first test, the press was set at a speed of 25 tablets per minute. In a second test, the press was set at a speed of 40 tablets per minute. This last speed corresponds to an industrial production of 250,000 tablets per hour.

[0171] The hardness of the tablets was measured using a durometer (PHARMATRON DT 50 503.0064).

[0172] The results obtained are presented in Figures 6 and 7.

[0173] At both speeds tested, it was found that the mannitol granules conforming to the description did not cleave, while PARTECK® M200 and PEARLITOL® 200 SD cleaved after 10-11 kN. Thus, it was the mannitol granules conforming to the description that achieved the highest hardnesses, up to approximately 250 N (at 16 kN Fc).

[0174] Additional compression tests were carried out on tablets containing an active pharmaceutical ingredient (results not shown here): the same trends were observed, i.e., mannitol granules conforming to the description did not cleave.

[0175] Thus, the mannitol granules according to the description allow the production of tablets of high hardness, at high production speed, compatible with industrial tablet production. Their resistance to cleavage makes it possible to increase the amounts of non-compressible ingredients (typically active ingredient) in the tablets and / or to reduce the size of the tablets. This is particularly advantageous for improving therapeutic compliance, especially in people with swallowing difficulties, for example in children, the elderly and / or individuals suffering from dysphagia.

[0176] The disintegration time of tablets prepared at a speed of 25 tablets per minute was evaluated according to a method in accordance with European Pharmacopoeia 7.1, 04 / 2011:20901, “2.9.1. Disintegration of tablets and capsules”. This disintegration time was 407 seconds on average (with a minimum of 398 seconds and a maximum of 418 seconds), which is well below 15 minutes, which is the maximum limit generally acceptable for standard, so-called “immediate release” tablets.

[0177] The mannitol granules conforming to the description have the qualities required for a compression excipient intended for industrial production of tablets. They allow correct filling of the matrices, i.e. filling uniform and reproducible distribution of a precise quantity of powder, and flow well in equipment used in direct compression. They are chemically and physically stable. They are cohesive enough to allow their transport or the production of mixtures. They do not hinder the bioavailability of the other ingredients of the powder and allow the production of tablets that dissolve well, in particular in contact with water. They allow the homogeneous mixing of the ingredients of the composition, and have a good absorption capacity. They allow the formulation of tablets with an acceptable texture and taste, which is necessary when the tablet is intended to be ingested. They generate packaging and transport costs that meet commercial standards, that is to say there is a good ratio between the mass of powder transported and the volume necessary to package this mass.

[0178] The mannitol granules according to the description were then used in the preparation of orodispersible tablets.

[0179] 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 (Vegetal magnesium stearate, WIGA PHARMA GMBH). The mannitol granules, melatonin and crospovidone were mixed for 5 minutes in an epicyclic 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 mixed for another 5 minutes.

[0180] The powders were compressed to obtain bevelled tablets with a diameter of 10 mm (upper and lower punches BEVEL EDGE D10 ref 2010060-5-1, matrix ref 2010060-1), having a weight of approximately 380 mg, and a hardness of approximately 75 N. 10% pre-compression was applied.

[0181] The press used was a single-punch development press that simulates compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM), controlled using ANALIS software, using the profile of the KORSCH XL 400. The press was set at a speed of 20 tablets per minute, which corresponds to an industrial production of 71,400 tablets per hour.

[0182] The disintegration rate of the tablets thus obtained was evaluated in vitro and in vivo.

[0183] The in vitro disintegration time of the tablets was evaluated according to a method in accordance with the European Pharmacopoeia 7.1, 04 / 2011:20901, “2.9.1. Disintegration of tablets and capsules”.

[0184] The dissolution time obtained was 30 seconds in vivo, and 10 seconds in vitro, when no pre-compression force was applied. It was 35 seconds in vivo, and 10 seconds in vitro, when a pre-compression force of 1.45 kN was applied. These dissolution times are excellent for orodispersible tablets.

[0185] Thus the mannitol granules according to the present description can be used as a compression excipient in standard tablets as well as in other tablets, for example in orodispersible tablets in particular when used in combination with at least one disintegrant, preferably a (super-)disintegrant.

[0186] D. Use of the granules according to this description in applications other than

[0187] The mannitol granules according to the present description have a lower electrostatic charge than that obtained with PEARLITOL® 200SD, a good flow and are not friable (section B.), which makes them an excellent candidate for use in filling containers for example capsules, sachets, and sticks, or for use in continuous processes, which require continuous mixing and dosing steps of powder. In addition, the mannitol granules according to the present description have a pleasant, slightly sweet taste, and possess a good dissolution profile. These qualities are particularly sought after for use in sachets or sticks, where the powder to be ingested comes into direct contact with the oral cavity. The mannitol granules according to the description also possess the qualities required for use in wet or dry granulation.

[0188] In order to confirm the potential of the granules in accordance with the invention in these applications, the following tests were carried out.

[0189] 1. Use for filling capsules

[0190] Mannitol granules according to the description were tested as a bulking agent for filling capsules. 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: after 1 mm sieving of the active ingredient, mannitol granules and LYCATAB® C, mixing at 40 rpm for 10 minutes (T2F, TURBULA), addition of magnesium stearate after 355 µm sieving, mixing at 40 rpm for 1 minute.The parameters used for capsule filling were as follows: FlexaLAB MG2 equipment (MG AMERICA); powder bed thickness 25 mm; dosing chamber filling height 13.5 mm; compression setting 1 mm; production speed 1000 capsules per hour; capsule size: size 1 (Capsugel®, Lonza); fill weight 270 mg; sampling interval 10 minutes. Capsule weight and disintegration time were measured at each sampling. Capsule disintegration time was determined on a disintegration tester (PTZ AUTO 3, Pharma Test) in demineralized water at 37°C.

[0191] The weight of the capsules was constant over time (350.38 ± 1.30 mg), as was the disintegration time (5.88 ± 1.11 minutes). These results confirm that the mannitol granules as described are suitable for use as a bulking agent for filling capsules.

[0192] 2. Use in wet granulation

[0193] 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 of propranolol (active ingredient), 62% by weight of mannitol granules, 3% by weight of pregelatinized corn starch (LYCATAB® PGS, ROQUETTE), 20% by weight of extra white corn starch. For granulation, 20% water was used, this percentage being expressed as the weight of water relative to the weight of the powder composition. Granulation was carried out as follows: - dry mixing in a high shear granulator (Diosna): 300 g of powdered composition sieved to 710 pm, mixing blade speed 250 rpm, for 180 seconds. - adding water to the granulator: Schlick atomizing nozzles, 60g of water, flow rate approximately 20g / min, for 3 minutes, mixing blade speed 500 rpm, lump crusher speed 1800 rpm. - granulation: mixing paddle speed 500 rpm, lump crusher speed 1800 rpm, 3 minutes. - wet grinding in a conical mill (Quadro® Comil®): calibration grid mesh 6350 pm, mesh type: square, rotor type: square, rotation speed 1000 rpm. - drying in a hot air oven: overnight at 60°C. - dry grinding in a conical mill (Quadro® Comil®): calibration grid mesh 1016 pm, mesh type: rasp, rotor type: square, rotation speed 1000 rpm.

[0194] The granulometry (method according to section B.4.), the tamped density, the aerated density and the water content were measured on the granular product obtained.

[0195] The granulated product had a uniform particle size distribution, with a volumetric D50 of approximately 200 μm. In contrast, the powder composition before granulation had a bimodal distribution. The aerated density was 680 g / L and the tapped density was 780 g / L. The Carr and Hausner indices calculated from the density values ​​were 12.59 and 1.14, respectively, indicating good flow of the resulting granulated product. These results show that the granules as described are suitable for use as a bulking agent in wet granulation.

[0196] 3. Use in dry granulation

[0197] The mannitol granules were then tested for use in dry granulation (by "slugging"). The powder composition to be granulated was as follows: 15% by weight of propanolol (active ingredient), 54% by weight of mannitol granules, 30% by weight of microcrystalline cellulose (MICROCEL® 102SD, ROQUETTE), 1% by weight of magnesium stearate. The composition was prepared as follows: after passing through a 710 μm sieve, mixing the propanolol, mannitol granules and microcrystalline cellulose at 40 rpm for 10 minutes (T2F, TURBULA), addition of magnesium stearate after sieving 355 μm, mixing at 40 rpm for 1 minute. The powdered composition was then compressed using the following parameters: STYL'One Evolution press (MEDELPHARM), punches and die: EU-B round, chamfered, 16 mm (Natoli), press speed 25 rpm (Fette P2090 Euro B 54000 tablets / hour), compression force approximately 17 kN, tablet weight 1 g. The hardness of the tablets obtained was measured using a durometer (ST50, SOTAX), and was approximately 115 N. The tablets obtained were ground. The dry grinding parameters were as follows: calibration grid mesh 1016 pm, mesh type: rasp, rotor type: square, rotation speed 3000 rpm.

[0198] The particle size distribution (method according to section B.4.) and the tapped density and aerated density were measured on the resulting granulated product. The granulated product had a relatively uniform particle size distribution, with a D50 by volume of approximately 130 μm. The aerated density was 610 g / L and the tapped density 780 g / L. The Carr and Hausner indices calculated from the density values ​​were 21.97 and 1.28 respectively, indicating a passable flow of the resulting granulated product. These results show that the granules as described are suitable for use as a filler in dry granulation, although the process parameters can still be optimized in this case.

Claims

Demands

1. Microcrystalline mannitol granules, characterized in that: - said mannitol has a crystalline P content greater than or equal to 90%; and, - they have a mean arithmetic volume diameter D(4;3) greater than or equal to 90 pm and less than or equal to 400 pm; and, - they have an aerated density greater than or equal to 600 g / L; and, - they have a specific surface area greater than or equal to 0.50 m² 2 / g.

2. Microcrystalline mannitol granules according to claim 1, characterized in that they have a crystalline form P content greater than or equal to 95%.

3. Microcrystalline mannitol granules according to claim 1 or 2, characterized in that they have an aerated density greater than or equal to 610 g / L.

4. Microcrystalline mannitol granules according to any one of claims 1 to 3, characterized in that they have a packed density greater than or equal to 650 g / L.

5. Microcrystalline mannitol granules according to any one of claims 1 to 4, characterized in that they have a specific surface area greater than or equal to 0.60 m² 2 / g.

6. Powdered composition comprising microcrystalline mannitol granules according to any one of claims 1 to 5, and at least one other ingredient.

7. A method for preparing tablets, comprising the direct compression of a powder composition according to claim 6.

8. Tablet composed of the powder composition according to claim 6, or capable of being obtained by, or obtained by the tablet preparation process according to claim 7.

9. Use of microcrystalline mannitol granules according to any one of claims 1 to 5, as a direct compression excipient, as a filler for filling capsules, sachets or sticks, and / or as a filler in shaping powders, for example by wet or dry granulation.

10. A mannitol granulation process characterized in that it is a continuous fluidized bed spray granulation process of a mannitol solution, wherein: - the temperature of the fluidized bed of the granulator is greater than or equal to 30°C and less than or equal to 70°C; and, - a fraction of the mannitol is recycled.

11. Mannitol granulation process according to claim 10, characterized in that the recycling rate is 30 to 70% by weight of the product which is extracted from the granulator.

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

13. Mannitol granulation process according to any one of claims 10 to 12, characterized in that the arithmetic mean volume diameter D(4;3) of the recycled mannitol particles is greater than or equal to 20 pm and less than or equal to 150 pm.

14. Mannitol granulation process according to claim 13, characterized in that the arithmetic mean volume diameter D(4;3) of the recycled mannitol particles is greater than 25 pm.

15. Mannitol granulation process according to any one of claims 10 to 14, characterized in that the sprayed mannitol solution has a dry matter by weight greater than or equal to 20%, and less than or equal to 50%.

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