Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
  • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• 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.
• Direct compression techniques allow the manufacture of tablets containing precise quantities of active ingredients, at rapid speed, and at relatively low cost.
• This technology consists of strongly compressing a powder composition in a matrix using two punches, so as to give it the shape of a tablet. The high pressure applied causes the powder particles to clump together and produce a solid tablet.
• These powder compositions typically comprise excipients and active ingredients of interest, for example pharmaceutical, veterinary, cosmetic, food, nutraceutical, chemical or agrochemical.
• diluents also called “direct compression excipients” in this case, lubricants, (super-)disintegrants, flow agents, pH stabilizers, colorants, flavors, surfactants.
• the pulverulent composition to be compressed always comprises at least one direct compression excipient and a lubricant.
• Direct compression excipients are the majority compounds in tablets and are responsible for the compressibility and flow properties of the powder.
• the most commonly used are microcrystalline cellulose and lactose.
• the lubricant allows the ejection of the matrices of the newly formed tablets. On some tablet presses, the lubricant is not mixed with other powders but sprayed directly onto the walls to be lubricated. It limits the stress induced by the ejection and therefore makes it possible to preserve the integrity of the tablets.
• the most commonly used is magnesium stearate, followed by calcium stearate and sodium stearyl fumarate.
• the direct compression excipient should make it possible to obtain tablets of sufficient hardness, in particular in order to guarantee their integrity over time, and in particular during the various handling, storage and transport.
• This hardness can be increased by increasing the compression force applied to the powder to be compressed.
• Fc compression force
• the use of high compression forces in order to obtain tablets of high hardness has its limits, however: there is indeed a limit Fc from from which phenomena of cleavage of the tablets appear.
• Cleavage takes the form of horizontal fracturing of the tablets, either in the middle or at the start of one of the two domed parts.
• Non-sensitivity to cleavage also makes it possible to do away with the cylindrical shape and to develop domed tablets that are easier to swallow - especially for patients who have long-term treatments - or tablets with attractive shapes (such as sun , star) in the fields of pediatrics and nutraceuticals. This also speeds up the throughput of tablet presses and therefore productivity.
• the object of the present invention is thus to provide a mannitol powder having improved compression behavior, in particular under compression conditions compatible with industrial production of tablets.
• the object of the present invention in particular is to provide a mannitol powder which makes it possible to manufacture tablets of high hardness, and/or which do not cleave easily.
• the present invention aims to respond to the aforementioned 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.
• the mannitol has a content of crystalline form P greater than or equal to 90%
• 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 ⁇ m.
• the inventors have even succeeded in obtaining granules in the range of 100-200 ⁇ m, which makes them particularly suitable for most pharmaceutical uses.
• the mannitol and the active agent have the same particle size.
• most pharmaceutical active agents have a particle size of 100-200 ⁇ m.
• the mannitol granules according to the present description have a lower electrostatic charge than that obtained with PEARLITOL® 200SD, good flow and have low friability, preferably are not friable (Examples, section B.), which makes it an excellent candidate for use for filling containers, for example capsules, sachets, and sticks (the sticks 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 powder dosing steps.
• 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 is in direct contact with the oral cavity.
• 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.).
• the mannitol granules according to the present description moreover have very advantageous properties for use as a bulking agent in wet or dry granulation (Examples, section D.).
• mannitol granules can be obtained by a continuous spray granulation process in a fluidized air bed of a mannitol solution, in which: - the temperature of the bed of the granulator is greater than or equal to 30° C. and less than or equal to 70° C.; And,
• This process makes it possible to obtain very good mechanical strength of the particles. Its productivity is good, and little variability is observed for the final properties compared to other processes, in particular compared to those carried out in batch mode.
• the process of the invention can make it possible to obtain powders low in fines (cf. FIG. 4B).
• this provides an additional benefit, which is that the mannitol granules exhibit consistent batch-to-batch behavior. A percentage of fines expressed in weight will be perceived as low, but the reality of the quantity of fines in number is totally different.
• these fines can generate many problems in compression: lack of flow, non-homogeneity, difficulty in lubrication, fouling of the press, static electricity. Poor control of the fines content or a variation thereof can therefore exert a negative influence on the compression behavior of the mannitol powder.
• An additional advantage of the method of the invention is therefore to offer the possibility of reducing these fines.
• a simple sieving does not solve this problem: mannitol has self-adhesion properties, in particular by static electricity and clogs the sieves very quickly.
• these fines are not effectively removed.
• the first subject of the invention is thus 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 volume mean diameter D(4;3) greater than or equal to 90 ⁇ m and less than or equal to 400 ⁇ m; And,
• said mannitol granules have a content of crystalline form P greater than or equal to 95%.
• said mannitol granules have an aerated density greater than or equal to 610 g/L.
• said mannitol granules have a packed density greater than or equal to 650 g/L.
• said mannitol granules have a specific surface area greater than or equal to 0.60 m 2 /g.
• the invention also relates to a powder composition
• a powder composition comprising the mannitol granules according to the present description, and at least one other ingredient.
• the invention also relates to a method for preparing tablets, comprising the direct compression of a powder composition according to the present description.
• the invention also relates to a tablet composed of the powder composition according to the present description, or capable of being obtained by, or obtained by the process for preparing tablets according to the invention.
• the invention also relates to the use of mannitol granules according to the present description, as a direct compression excipient, as a bulking agent for filling capsules, sachets or sticks, and/ or as bulking agent in the shaping of powders, for example by wet or dry granulation.
• the invention also relates to a process for granulating mannitol, characterized in that it is a continuous process for spray granulation 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;
• the recycling rate is 30 to 70% by weight of the product which is extracted from the granulator. It is still preferably greater than or equal to 35% by weight of the product which is extracted from the granulator.
• the arithmetic mean diameter by volume D(4;3) of the recycled mannitol particles is greater than or equal to 20 ⁇ m and less than or equal to 150 ⁇ m. It is still preferably greater than 25 ⁇ m.
• the sprayed mannitol solution has a dry matter by weight greater than or equal to 20%, and less than or equal to 50%.
• Figure 1 represents an example of a diagram of a method according to the invention.
• Figure 2 is a characterization table of mannitol powders in accordance with the invention and of comparative mannitol powders.
• FIG. 3A [Fig. 3B] [Fig. 3C] [Fig. 3D] [Fig. 3E]
• Figures 3A, 3B, 3C, 3D, and 3E are photographs taken with a scanning electron microscope, of mannitol powders in accordance with the invention (3A, 3B, 3C) and of comparative mannitol powders (3D, 3E ).
• Figure 4 [0040] [Fig. 4A] [Fig. 4B] Figures 4A and 4B are particle size distributions by number of mannitol powders according to the invention (4B) and comparative mannitol powders (4A).
• Figure 5 represents compression curves of mannitol powders in accordance with the invention, obtained on the KORSCH XP1 single-punch press.
• 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 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).
• 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%
• mannitol granules conventionally refers to particles of mannitol which, observed under an electron microscope, at a magnification for example of X100, appear of variable shapes, in particular non-spherical, and of irregular surface. .
• 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).
• the particles of PEARLITOL® 200 SD presented in Figure 3D although they can also be qualified as mannitol granules, do not have this raspberry shape, and have a smoother surface than the mannitol granules according to this description.
• the mannitol granules according to the present description have little porosity, at a magnification for example of X3000.
• microcrystalline typically refers to a structure which, observed under an electron microscope at a magnification of, for example, X3000, essentially presents microcrystals on the surface and very rarely larger crystals.
• a microcrystal can be defined as a crystal whose sum of length, width and thickness is less than 25 ⁇ m.
• the microcrystals can have very different shapes, from rounded 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.
• the mannitol granules according to the present description are easily differentiated from conventional crystalline mannitol powders, composed of well individualized macrocrystals, typically polyhedral, of regular surface, of substantially constant thickness but of variable length and width, generally obtained by simple crystallization in water, from a solution supersaturated with mannitol. They are further differentiated from mannitol powders obtained by agglomeration of a powder composed of mannitol macrocrystals.
• the mannitol granules according to the present description also differ from the 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 ⁇ m (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).
• mannitol powders obtained by melting/extrusion, which are formed of more compact and more regular particles, in the form of more or less angular cobblestones, and which consist of generally oriented microcrystals.
• the mannitol granules as described can typically be obtained by a spray granulation process, a process in which mannitol granules are formed from a mannitol solution.
• the microcrystalline mannitol granules according to the present description can be defined by the fact that they are granulated, or that they are obtained, or capable of being obtained, by spray granulation, in in particular by a process of granulation by spraying in a fluidized air bed (“fluidized bed spray-granulation” in English).
• the mannitol granules according to the present description can 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.
• the mannitol granules according to the present description are also characterized in that the mannitol comprises at least 90% of crystalline form p.
• the crystalline polymorphism of mannitol can be determined by those skilled in the art by infrared spectrometry or by X-ray powder diffraction, preferably by X-ray powder diffraction. It is for example possible to proceed according to the method as described in the Examples section below.
• 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 P crystal form percentages are typically expressed as a function of the total represented by the a, P, and 5 crystal forms.
• the mannitol granules according to the present description are also characterized in that they have an arithmetic mean diameter by volume D(4;3) greater than or equal to 90 and less than or equal to 400 ⁇ m.
• This arithmetic mean diameter by volume D(4;3) is preferably greater than or equal to 100 ⁇ m, preferably greater than or equal to 120 ⁇ m, preferably greater than or equal to 140 ⁇ m, preferably greater than or equal to 150 ⁇ m, preferably greater than or equal to 160 ⁇ m, preferably greater than or equal to 170 ⁇ m, preferably greater than or equal to 180 ⁇ m, or even greater than or equal to 190 ⁇ m.
• This arithmetic volume mean diameter D(4;3) can in particular be determined by a person skilled in the art by means of a laser diffraction particle size analyzer in the dry process, for example according to the method as described in the Examples section below. After.
• the mannitol granules in accordance with the description have a D10 in number greater than or equal to 20 ⁇ m, preferably greater than or equal to 30 ⁇ m, preferably greater than or equal to 40 ⁇ m, 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 ⁇ m, or even less than or equal to 120 ⁇ m, even less than or equal to 100 ⁇ m, even less than or equal to 80 ⁇ m, or even less than or equal to 70 ⁇ m.
• the mannitol granules in accordance with the description have a D50 in number greater than or equal to 30 ⁇ m, preferably greater than or equal to 50 ⁇ m, preferably greater than or equal to 70 ⁇ m, preferably greater than or equal to 80 ⁇ m, preferably greater than or equal to 90 ⁇ m. It is generally less than or equal to 200 ⁇ m, even less than or equal to 150 ⁇ m, even less than or equal to 140 ⁇ m, even less than or equal to 130 ⁇ m, even less than or equal to 120 ⁇ m, even less than or equal to 110 ⁇ m, or even less than or equal to 100 ⁇ m.
• the mannitol granules in accordance with the description have a D90 in number greater than or equal to 80 ⁇ m, preferably greater than or equal to 100 ⁇ m, preferably greater than or equal to 110 ⁇ m, preferably greater than or equal to 120 ⁇ m, preferably greater than or equal to 130 ⁇ m, preferably greater than or equal to 140 ⁇ m, preferably greater than or equal to 150 ⁇ m. It is generally less than or equal to 300 ⁇ m, even less than or equal to 250 ⁇ m, even less than or equal to 200 ⁇ m, even less than or equal to 190 ⁇ m, even less than or equal to 180 ⁇ m, even less than or equal to 170 ⁇ m, or even less than or equal to 160 ⁇ m.
• the mannitol granules in accordance with the description have a D10 by volume greater than or equal to 50 ⁇ m, preferably greater than or equal to 60 ⁇ m, preferably greater than or equal to 70 ⁇ m, preferably greater than or equal to 80 pm. It is generally less than or equal to 200 ⁇ m, or even less than or equal to 150 ⁇ m, even less than or equal to 120 ⁇ m, even less than or equal to 110 ⁇ m, or even less than or equal to 100 ⁇ m.
• the mannitol granules in accordance with the description have a D50 by volume greater than or equal to 100 ⁇ m, preferably greater than or equal to 120 ⁇ m, preferably greater than or equal to 140 ⁇ m, preferably greater than or equal to 150 p.m. It is generally less than or equal to 250 ⁇ m, or even less than or equal to 200 ⁇ m, even less than or equal to 180 ⁇ m, or even less than or equal to 170 ⁇ m.
• the mannitol granules in accordance with the description have a D90 by volume greater than or equal to 200 ⁇ m, preferably greater than or equal to 250 ⁇ m, preferably greater than or equal to 260 ⁇ m, preferably greater than or equal to 280 ⁇ m, preferably greater than or equal to 300 ⁇ m, preferably greater than or equal to 310 ⁇ m, preferably greater than or equal to 320 ⁇ m, preferably greater than or equal to 330 ⁇ m. It is generally less than or equal to 450 ⁇ m, or even less than or equal to 400 ⁇ m, even less than or equal to 380 ⁇ m, even less than or equal to 370 ⁇ m, or even less than or equal to 360 ⁇ m.
• 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 by volume are the sizes for which 10%, 50% and 90% respectively by volume of the particles have a smaller particle size.
• the values of D10, D50 and D90 in number or in volume can in particular be determined by those skilled in the art by means of a laser diffraction particle size analyzer in the dry process, for example according to the method as described in the Examples section below.
• the mannitol granules in accordance with the description are also characterized in 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.
• 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, even less than or equal to 800 g/L, even less than or equal to 790 g/L, even less than or equal to 780 g/L, even less than or equal to 770 g/L. 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.
• This aerated density and this packed density can be determined by those 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.
• the mannitol granules in accordance with 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 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 is generally less than or equal to 3.00 m 2 /g, or even less than or equal to 2.50 m 2 /g, or even 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 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.
• the mannitol granules in accordance with the description can also be characterized in that they are mannitol for direct compression or mannitol "directly compressible”. It is also conventionally referred to as “direct compression excipient”.
• the mannitol granules in accordance with the description can thus be compressed directly, that is to say without any prior texturing treatment or physical transformation, 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 amount” is such that it effectively allows the formation of tablets, that is to say typically, that there is absence of sticking, seizing, and that the force of ejection of the tablet from the press is less than 1000 Newtons, on a production for example of 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 the "seizing” corresponds to the sticking of part of the material on the matrix, sticking which persists after ejection of the tablet. Seizure is visible on the tablet: vertical stripes are present and correspond to the locations where the product has remained stuck to the matrix.
• This ability to form satisfactory tablets can be determined, for example, by direct compression of a pulverulent composition consisting of the excipient to be tested and lubricant, for example magnesium stearate, so as to form convex tablets of 10 mm in diameter with a radius of curvature of 9 mm, and a weight of 400 mg. Tablets can be formed therefrom by means of a rotary press, or by means of 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 speed of the press can 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.
• test A 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.
• the mannitol granules of the present description preferably have a maximum compressibility (when the Fc is varied, 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.
• 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 to 300 N, even less than or equal to 250 N, even less than or equal to 230 N, even less than or equal to 210 N, even less than or equal to 200 N.
• the mannitol granules in accordance with the description can 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 tabletability (400 mg tablets, convex, 10 mm in diameter and with a radius of curvature of 9 mm, obtained on a mono-developing press). punch that simulates compression on an industrial rotary press, using a rate of 25 or 40 tablets per minute).
• the mannitol granules of the present description do not cleave at all according to this test. Note that according to this test again, you cannot compress with forces greater than 25 kN, because you risk damaging the punch. Indeed, concave-shaped punches are more fragile and support lower maximum Fc, because their edge is thinned.
• the mannitol granules according to the present description have a flow note 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 note can be determined by those 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”.
• 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”. It is possible, for example, to proceed according to the method as described in the Examples section below.
• 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 a person skilled in the art using the GRANUCHARGETM instrument, for example according to the method as described in the examples below.
• the mannitol granules of the present description are mannitol, but these granules can however comprise other ingredients, in small quantities, and as long as this does not contravene the properties sought in the present invention.
• binders such as polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), cellulose derivatives, gum acacia, gelatin, starch derivatives such as maltodextrins, gum tragacanth; minerals; carbohydrates such as sugars and sugar alcohols other than mannitol; food additives, colorants; nutraceutical, pharmaceutical, veterinary or cosmetic active ingredients; curators; stabilizers.
• PVP polyvinylpyrrolidone
• CMC carboxymethylcellulose
• HPMC hydroxypropylmethylcellulose
• the content of other ingredients in the granules is less than 15.0%, preferably less than 10.0%, preferably less than 5.0%, preferably less than 2 0.0%, preferably less than 1.0%, even more preferably less than 0.5%; these percentages being expressed by weight relative to the total weight of granules.
• 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.
• the mannitol according to the present description preferably has a richness in mannitol, in particular in 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.
• Impurities typically include mannitol related substances, especially 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”).
• the mannitol granules according to the present description have a mass loss on drying of 0.00 to 0.50% by weight. This mass loss on drying is preferably less than or equal to 0.40% by weight, preferably less than or equal to 0.30%.
• the present invention also relates to a process for the granulation of mannitol, which is particularly useful for the manufacture of the mannitol granules described above, characterized in that it is a continuous process of granulation by spraying in a bed of fluidized air 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.
• 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 the drying of this solution on a primer obtained by recycling a fraction of the granulated particles previously obtained.
• the process in accordance with the description does not involve “exogenous” mannitol powder, that is to say other than that generated by the mannitol solution; except for negligible quantities of mannitol powder which may be used at the start of the process for initial priming.
• 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.
• the fluidization air flow is typically chosen so as to have a linear speed in the bed of between 1.0 and 2.0 m/s, preferably around 1.5 m/s.
• the fluidization air temperature is typically adjusted to control the temperature of the fluidized bed. It is for example greater than or equal to 100°C, and less than or equal to 150°C. It is for example greater than or equal to 110° C., or even greater than or equal to 120° C. It is for example less than or equal to 140° C. It is for example approximately equal to 130° C.
• the fluidized bed used is a circular fluidized bed.
• 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 from a range of about 38 to about 40%.
• the sprayed mannitol solution is maintained at a temperature (“supply temperature”) making it possible to maintain the mannitol in solution.
• 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.
• the spraying is carried out by means of bi-fluid spray nozzle(s). Their number will conventionally be adapted to the size of the fluidized bed. These nozzles can be placed either at the top (“top spray”) or at the bottom (“bottom spray”) of the fluidized bed.
• the solution feed rate is greater than or equal to 300 kg/h/m 2 of fluidized bed, and less than or equal to 400 kg/h/m 2 of fluidized bed. It is preferably greater than or equal to 310 kg/h/m 2 of fluidized bed, preferably greater than or equal to 320 kg/h/m 2 of fluidized bed.
• It is preferably less than or equal to 380 kg/h/m 2 of fluidized bed, preferably less than or equal to 350 kg/h/m 2 of fluidized bed, preferably less than or equal to 340 kg/h/m 2 of fluidized bed. It is for example approximately equal to 330 kg/h/m 2 of fluidized bed.
• 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 bars, preferably greater than or equal to 2.0 bars, preferably greater than or equal to 2.5 bars. It is preferably less than or equal to 3.5 bars, preferably less than or equal to 3.0 bars.
• 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. vs. It is for example approximately equal to 25°C.
• the particles having a size greater than or equal to 50 ⁇ m, preferably greater than or equal to 80 ⁇ m, preferably greater than or equal to approximately 100 ⁇ m 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) do not generally make it possible to obtain a clean cut.
• this extraction is ensured by means of an air classifier unloading tube.
• the particle size threshold for classification is set by the classification airflow.
• the classification air flow chosen so as to have a linear speed in the tube comprised between 2.0 and 5.0 m/s preferably comprised between 3.0 and 4.5 m/s and preferably between 3.3 and 3.8 m/s.
• the method in accordance with the description comprises a step of cooling the mannitol granules, after extraction from the granulator. This step is preferably provided by means of a vibrated fluidized air bed.
• the method in accordance with the description comprises the recycling of granulated particles of mannitol, in particular fine ones.
• the recycled fraction is reintroduced in dry form, that is to say that the granulated particles of mannitol are not resolubilized in solution but directly reinjected into the bed of the granulator.
• the recycled particles typically come from the mannitol extracted from the granulator. They are recycled as is, or after shredding.
• 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 extracted mannitol, for example using the classifier.
• the mannitol extracted from the granulator undergoes a step for separating the particles considered to be too fine, and/or a step for separating the particles considered to be too large, preferably both.
• the particles considered too fine will feed the recycling system without any grinding being necessary.
• the particles considered too large will feed the recycling system after shredding.
• this separation is carried out after a cooling step, in particular as described before.
• the recycling rate is 30 to 70% by weight of the product extracted from the granulator.
• 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%.
• the mean diameter of the recycled mannitol particles is less than the mean particle diameter ultimately desired.
• the arithmetic mean diameter by volume D(4;3) of the recycled mannitol particles is preferably greater than or equal to 20 ⁇ m and less than or equal to 150 ⁇ m. It is preferably greater than 25 ⁇ m, preferably greater than 50 ⁇ m, preferably greater than 75 ⁇ m, preferably greater than or equal to 80 ⁇ m. It is preferably less than or equal to 150 ⁇ m, preferably less than or equal to 140 ⁇ m, preferably less than or equal to 130 ⁇ m, preferably less than or equal to 120 ⁇ m.
• the cut-off threshold used for the particles considered to be too fine is greater than or equal to 50 ⁇ m and less than or equal to 150 ⁇ m. It is preferably greater than or equal to 80 ⁇ m, preferably greater than or equal to 90 ⁇ m. It is preferably less than or equal to 130 ⁇ m, preferably less than or equal to 110 ⁇ m. This cut-off threshold is for example equal to around 100 ⁇ m.
• the fraction which passes is typically and preferably introduced as such (without undergoing grinding) into the recycling system.
• the cut-off threshold used for the particles considered to be too large is greater than or equal to 400 ⁇ m and less than or equal to 800 ⁇ m.
• the retained fraction is typically and preferably introduced into the recycling system after grinding.
• these sievings are carried out in series.
• the sieves are organized from the highest to the lowest cut-off threshold.
• the sieving aimed at separating the particles considered to be too large is carried out before the sieving aimed at separating the particles considered to be too fine.
• the method comprises an initial initiation step, in order to allow the start of the granulation.
• powdered mannitol is introduced into the fluidized bed. One will typically fill between half and the whole of the bed with this mannitol powder.
• this quantity of mannitol is less than or equal to 300 kg/m 2 of fluidized bed. It is recalled that this “exogenous” mannitol represents a very small amount of mannitol relative to the total amount of mannitol used. For example, 200 to 600 kg of powder will be used to produce 7 tons of mannitol granules over 24 hours. Thus typically, the quantity of mannitol used for the initial priming is preferably less than or equal to 10% relative to the weight of the mannitol granules produced, and will tend towards 0% after several days of continuous production.
• a crystallized mannitol powder (composed of mannitol macrocrystals) is used for the initial initiation.
• textured mannitol for example atomized or granulated.
• the granulation process in accordance with the description includes the implementation of these other ingredients, which can 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 a solution, for example via the sprayed mannitol solution.
• the granulation process comprises:
• step i2) optionally, cooling the mannitol particles from step i2), preferably in a fluidized air bed;
• step i2) sieving the mannitol particles from step i2) or from step i3) so as to obtain:
• - mannitol granules having an arithmetic mean diameter by volume D(4;3) greater than or equal to 90 ⁇ m and less than or equal to 400 ⁇ m, and, optionally: - mannitol particles having a diameter of less than 130 ⁇ m, preferably less than 110 ⁇ m, preferably less than 100 ⁇ m, (particles which can also be designated by the term “fines”), and/or
• - mannitol particles having a diameter greater than 400 ⁇ m, preferably greater than 450 ⁇ m, preferably greater than 500 ⁇ m, (particles which can also be designated by the term “refusal”);
• the mannitol granules of step i4) conform to the mannitol granules of the present description.
• the recycling rate is as defined above.
• 30 to 70% by weight of the mannitol particles resulting from stage i2) are recycled according to stage i5) and stage i6).
• step i2) 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).
• the method also comprises an initial initiation step iO), in which the bed of the fluidized air bed granulator is supplied at the start of the method with a mannitol powder.
• a mannitol powder One will typically fill between half and the whole of the bed with this mannitol powder.
• the arithmetic mean diameter by volume D(4;3) of the recycled mannitol particles is as defined before, in particular is greater than 25 ⁇ m.
• the present invention also relates to a pulverulent composition, in particular a pulverulent composition for direct compression, comprising the mannitol granules in accordance with the description and at least one other ingredient.
• a pulverulent composition in particular a pulverulent composition for direct compression, comprising the mannitol granules obtained or likely to be obtained according to the granulation process in accordance with the description, and at least one other ingredient.
• This pulverulent composition preferably consists of:
• 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;
• 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
• directly compressible sugars such as the directly compressible forms of sucrose, dextrose, dextrates, lactose, allulose
• dispersants or disintegrants such as sodium starch glycolate, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone (PVP), starches;
• - granulating agents such as polyvinylpyrrolidone, cellulose derivatives, gum acacia, dextrose, gelatin, maltodextrins, starches, starch derivatives, gum tragacanth;
• flavourings such as flavourings, acidifiers
• - dyes such as mineral dyes, pigments or soluble dyes
• - flow agents for example silica dioxide
• anti-adherent agents for example talc
• active ingredients in particular pharmaceutical, veterinary, nutraceutical or cosmetic.
• the pulverulent 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 pulverulent 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%.
• the powder composition in accordance with the description comprises a disintegrant, preferably a super-disintegrant.
• tablette conventionally means within the meaning of the present description, a solid preparation obtained by direct compression of a powder composition.
• the tablet may for example be intended for food, pharmaceuticals, cosmetics, nutraceuticals. These may be tablets to suck, chew, swallow, orodispersible tablets, effervescent tablets. These tablets can be intended for humans, adults or children, or for animals. It can also be tablets for chemical or agrochemical purposes. These tablets can be single-layered or multi-layered. In the present description, the tablets are preferentially domed or in other words convex.
• mannitol granules Use of mannitol granules
• the present invention also relates to the use of mannitol granules in accordance with the description as a direct compression excipient, as a bulking agent for filling capsules, sachets or sticks, and/or as a bulking agent in the shaping of powders, for example by wet or dry granulation.
• the present invention also relates to the use of mannitol granules in accordance with 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 compaction.
• the granules in accordance with the description are used as bulking agent.
• 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 bulking agent for filling capsules, sachets or shives, and/or as bulking agent in the shaping of powders, for example by wet or dry granulation.
• the amounts of ingredients are generally expressed in percentages by weight. Unless otherwise stated, these weights are amounts of ingredients as is in their powder or oily form. Powdery ingredients usually contain small amounts of water (also called % moisture or “drying mass loss”) and some impurities.
• mannitol granule powders were prepared by spray granulation in a fluidized air bed.
• the process was carried out according to the diagram shown in Figure 1.
• the granulator provided with a fluidized bed (AGT type granulator diameter 1700 mm) was fed with a mannitol solution at 38% dry matter.
• the fluidized bed of the granulator was filled with 600 kg of powdered mannitol (mannitol crystals with an average diameter equal to approximately 120 ⁇ m (PEARLITOL®
• the sprayed solution was granulated in a circular fluidized bed.
• Sieving was carried out continuously on a three-stage ALLGAIER TSM 2000/3 nutation sieve equipped with a 100 ⁇ m screen with ultrasonic heads and a 500 ⁇ m screen. Particles smaller than 100 ⁇ m (considered too fine) were recycled directly, while particles larger than 500 ⁇ m (considered too large) were ground on a PAS 500 POITTEMILL type grinder and then reintroduced into the granulator chamber, via the recycling system. The 100-500 ⁇ m cut was continuously collected to obtain the finished product.
• the specific surface areas 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, in according to the technique described in the article BET Surface Area by Nitrogen Absorption by S. BRUNAUER et al. (Newspaper of American Chemical Society, 60, 309, 1938). The BET analysis was performed at 3 points.
• the crystalline forms of mannitol were determined by comparing the positions of the diffraction lines of the sample with respect to the mannitol databases (Alpha ref CSD1142501; Beta ref CSD1142500; Delta ref CSD 662815), corresponding to the references of the alpha forms, beta and delta of mannitol.
• the quantitative analysis was carried out using the Rietveld method with the Topas V6 software (in the case of a Bruker spectrometer), using the fundamental parameters approach from the structure files available on the COD databases (Crystallography Open Database) and CSD (Cambridge Structural Database).
• the determination of the proportions of polymorphs of the alpha, beta and delta types was carried out by simulating a diffractogram from the cif files of the reference products and after refining the various crystallographic parameters.
• Particle size average diameter D(4;3) and size distribution of number or in .
• D90 (by number or by volume) of the mannitol powders was measured by dry laser diffraction, applying the Fraunhofer theory. The measurement was carried out with the MASTERSIZER 3000 (MALVERN) equipment in a dry process (the dispersion accessory was the Aero S), following the technical manual and the manufacturer's specifications.
• the dispersal attachment 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 ⁇ m to 3500 ⁇ m. Obscuration was targeted between 8% and 10%. 2 measurements were made for each sample. The result is the average of the two measurements.
• the data read in number mode were the same diameters (except the D(4;3) which is always in volume).
• Electrostatic charge The electrostatic charge was measured using the GRANUCHARGETM.
• the GRANUCHARGETM instrument automatically and accurately measures the amount of electrostatic charges 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 the flow inside the V-tube.
• the free flow properties of the powder made it possible to use the simple beaker rotation method to feed the stainless steel tubing circuit.
• the quantity of powders used to make a measurement can vary between 20-50g. No recycling can be performed after a measurement.
• Three different couples [temperature/humidity] were selected to evaluate their influences on the electrostatic charge obtained. 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)).
• the press used was a single-punch development press which simulates compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM), controlled using the ANALIS software, using the standard profile of the STYLCAM® .
• This press advantageously makes it possible to simulate 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. The hardness of the tablets was measured using a durometer (PHARMATRON DT 50 503.0064).
• mannitol granules according to the present description can be used as 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.
• the mannitol granules in accordance with the description were tested as filler for filling capsules.
• the pulverulent 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% in 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), adding magnesium stearate after 355 sieving pm, mix at 40 rpm for 1 minute.
• the parameters used for capsule filling were: FlexaLAB MG2 equipment (MG AMERICA); powder bed thickness 25 mm; filling height of the dosing chamber 13.5 mm; 1mm compression adjustment; production speed 1000 capsules per hour; capsule size: size 1 (Capsugel®, Lonza); fill weight 270mg; sampling interval 10 minutes.
• the weight and disintegration time of the capsules were measured at each sampling.
• the disintegration time of the capsules was determined on a disintegration tester (PTZ AUTO 3, Pharma Test) in deionized water at 37°C.
• the weight of the capsules was constant over time (350.38 ⁇ 1.30 mg), as was the disintegration time (5.88 ⁇ 1.11 minutes).
• 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 cornstarch.
• 20% water was used, this percentage being expressed as weight of water relative to the weight of the powder composition.
• the granulation was carried out as follows:
• the granulated product had a uniform particle size, with a volume D50 of about 200 ⁇ m.
• the powder composition before granulation exhibited a bimodal distribution.
• the aerated density was 680 g/L and the tapped density 780 g/L.
• the Carr and Hausner indices calculated from the density values were 12.59 and 1.14 respectively, which is the sign of good flow of the granulated product thus obtained.
• 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 propranolol (active ingredient), 54% by weight of mannitol granules, 30% by weight of microcrystalline cellulose (MICROCEL® 102SD, ROQUETTE), 1% by weight of stearate of magnesium.
• the composition was prepared as follows: after passing through a 710 ⁇ m sieve, mixing propanolol, mannitol granules and microcrystalline cellulose at 40 rpm for 10 minutes (T2F, TURBULA), addition of magnesium stearate after sieving at 355 ⁇ m, mixing at 40 rpm for 1 minute.
• the powder 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 about 17 kN, tablet weight 1g.

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