Directly compressible mannitol granules

Abstract

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

Description

[Technical Field]

[0001] This invention relates to compressible mannitol granules and a process for preparing them. The invention also relates to the use of compressible mannitol granules for the preparation of tablets, particularly by direct compression. [Background technology]

[0002] Direct compression technology makes it possible to produce tablets containing precise amounts of active ingredients quickly and at relatively low cost. This technology involves strongly compressing a powdered composition in a die using two punches to give it the shape of a tablet. The applied high pressure causes the powder particles to aggregate, producing a solid tablet.

[0003] These powdered compositions typically contain excipients and the target active ingredient, such as the active ingredient for pharmaceuticals, veterinary medicines, cosmetics, foods, nutritional supplements, chemicals, or pesticides.

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

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

[0006] Direct compression excipients should ensure that tablets have sufficient hardness over time, particularly during handling, storage, and transport, to guarantee their integrity. This hardness can be increased by increasing the compression force applied to the powder being compressed. The higher the compression force (Fc), the denser and harder the resulting tablets will be. However, when mannitol powder is used as a direct compression excipient, there are limits to the use of high compression forces to produce high-hardness tablets; beyond which there is a threshold Fc beyond which tablet stacking occurs. Stacking (including capping and flaking) takes the form of horizontal crushing of the tablet, either in the center or at the beginning of one of the two dome-shaped portions.

[0007] In the market for directly compressed mannitol, PARTECK® M200 (MERCK) is currently the most difficult to obtain. However, as explained above, the stacking phenomenon appears when the Fc applied to PARTECK® M200 is increased, and as a result, it is not possible to achieve a certain hardness. It is advantageous to have a mannitol powder that can be used to obtain even harder tablets. This makes it possible, for example, to increase the amount of incompressible material in the tablet formulation. It is also advantageous to have a mannitol powder that does not stack easily, in order to give a greater degree of freedom with respect to the compression parameters used, in particular to avoid a pre-compression step that is impossible to perform if the compression press is not equipped with one. Insensitivity to stacking also makes it possible to eliminate cylindrical shapes and develop dome-shaped tablets that are easy to swallow, especially for patients undergoing long-term treatment, or tablets with attractive shapes (sun, star, etc.) in the fields of pediatrics and nutritional supplements. This also accelerates the output of the tablet press and, consequently, productivity.

[0008] Subject matter of the present invention Therefore, an object of the present invention is to provide mannitol powder having improved compression behavior, particularly under compression conditions suitable for industrial tablet production.

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

[0010] The present invention aims to solve the above-mentioned problems by proposing a mannitol excipient that further possesses other properties required for direct compression excipients, for example, with respect to particle size, flow, or dissolution.

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

[0012] These microcrystalline mannitol granules are - Mannitol has a crystalline β content of 90% or more, - The microcrystalline mannitol granules have a volume-average diameter D(4;3) of 90 μm or more and 400 μm or less. - Microcrystalline mannitol granules have an air permeability density of 600 g / L or more. - Microcrystalline mannitol granules, 0.50 ml 2 It is characterized by having a specific surface area of ​​1 / g or more.

[0013] As can be seen from the following examples, at compression rates suitable for industrial tablet production, these mannitol granules do not stack even when an extreme compressive force (Fc) of 25 kN is applied. Conversely, PARTECK® M200 and PEARLITOL® SD stack after 10 kN.

[0014] Therefore, while it was possible to obtain tablets with a hardness of approximately 250 N using the mannitol granules of this disclosure, the maximum hardness was 168 N when using PARTECK® M200 (see Figure 6). In fact, PARTECK® M200 provides excellent compressibility up to approximately 10 kN Fc, but nevertheless laminates at higher Fc. Finally, the mannitol granules of this disclosure provide the highest hardness due to their resistance at high Fc.

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

[0016] The mannitol granules according to the present disclosure have a lower electrostatic charge, good flowability and low friability than those obtained using PEARLITOL® 200SD, and are preferably not friable (Examples, Section B), and are, for example, capsules, sachets and logs (logs are generally single-dose sachets having a longitudinal, usually tubular shape, called "stick packs") for use as container fillers, or excellent candidates for use in continuous processes that require continuous powder mixing and dosing steps. In addition, the mannitol granules according to the present disclosure have a pleasant slightly sweet taste and a good dissolution profile. These qualities are particularly required for use in sachets or logs where the powder to be ingested comes into direct contact with the oral cavity.

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

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

[0019] These mannitol granules can be obtained by a continuous process of spray granulation in a fluidized air bed of a mannitol solution. - The granulation machine bed temperature is 30°C or higher and 70°C or lower, - A part of mannitol is recycled.

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

[0021] In addition to obtaining mannitol granules with improved compressibility, the process of the present invention can produce a powder having a low fines content (see Figure 4B). One hypothesis is that this provides the further advantage that the mannitol granules behave consistently between batches. The percentage of fines is perceived as low when expressed by weight, but the actual amount of fines is quite different when expressed by number. However, these fines can cause many problems in compression, namely lack of flow, inhomogeneity, lubrication difficulties, press clogging and static electricity. Therefore, insufficient control or variation of the fines content can have an adverse effect on the compression behavior of mannitol powder.

[0022] Therefore, a further advantage of the process of the present invention is the possibility of reducing these fines. In fact, this problem is not improved by simple sieving, and mannitol has self - adhesiveness especially due to static electricity, which very rapidly clogs the sieve. Furthermore, since a large amount of fines remains attached to larger particles during sieving, these fines are not effectively removed. Therefore, instead of removing them, their formation can be avoided in the process of the present invention, while ensuring a satisfactory average size for the final product.

Summary of the Invention

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

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

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

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

[0027] Preferably, the mannitol granules are 0.60 mg 2 It has a specific surface area of ​​1 / g or more.

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

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

[0030] The subject matter of the present invention also includes tablets that can be obtained by a process for preparing tablets according to the present invention, or that consist of the powdered composition according to the present disclosure, or tablets that can be obtained by a process for preparing tablets according to the present invention.

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

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

[0033] Preferably, in this process, the recycling rate is 30 to 70% by weight of the product extracted from the granulator. Preferably, this is 35% by weight or more of the product extracted from the granulator.

[0034] Preferably, in this process, the volume-average diameter D(4;3) of the recycled mannitol particles is 20 μm or more and 150 μm or less. Preferably, this is greater than 25 μm.

[0035] Preferably, in this process, the mannitol solution sprayed contains 20% or more by weight and 50% or less by weight of dry material. [Brief explanation of the drawing]

[0036] Other features, details, and advantages of the present invention will emerge from reading the detailed description below and from analyzing the accompanying drawings. [Figure 1] An illustrative diagram of the process according to the present invention is shown. [Figure 2] This is a table of properties of the mannitol powder according to the present invention and a comparative mannitol powder. [Figure 3A] These are scanning electron microscope images of mannitol powders (3A, 3B, 3C) and comparative mannitol powders (3D, 3E) according to the present invention. [Figure 3B] These are scanning electron microscope images of mannitol powders (3A, 3B, 3C) and comparative mannitol powders (3D, 3E) according to the present invention. [Figure 3C] These are scanning electron microscope images of mannitol powders (3A, 3B, 3C) and comparative mannitol powders (3D, 3E) according to the present invention. [Figure 3D]These are scanning electron microscope images of mannitol powders (3A, 3B, 3C) and comparative mannitol powders (3D, 3E) according to the present invention. [Figure 3E] These are scanning electron microscope images of mannitol powders (3A, 3B, 3C) and comparative mannitol powders (3D, 3E) according to the present invention. [Figure 4A] This shows the particle size distribution by number of mannitol powders (4B) and comparative mannitol powders (4A) according to the present invention. [Figure 4B] This shows the particle size distribution by number of mannitol powders (4B) and comparative mannitol powders (4A) according to the present invention. [Figure 5] The compression curve of the mannitol powder according to the present invention, obtained using a KORSCH XP1 single punch press, is shown. [Figure 6] The compression curves for the mannitol powder according to the present invention and for comparative mannitol powder are shown. The tablets were prepared at a rate of 25 tablets / minute using a single-punch development press simulating compression in an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM). [Figure 7] The compression curves for the mannitol powder according to the present invention and for comparative mannitol powder are shown. The tablets were prepared at a rate of 40 tablets / minute using a single-punch development press simulating compression in an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM). [Modes for carrying out the invention]

[0037] Mannitol granules The present invention relates, firstly, to microcrystalline mannitol granules, - The mannitol has a β-crystal content of 90% or more, - The microcrystalline mannitol granules have a volume-average diameter D(4;3) of 90 μm or more and 400 μm or less. - Microcrystalline mannitol granules have an air permeability density of 600 g / L or more. - Microcrystalline mannitol granules, 0.50 ml2 This invention relates to microcrystalline mannitol granules characterized by having a specific surface area of ​​1 / g or more.

[0038] The term "mannitol granules" typically refers to mannitol particles that, when observed under an electron microscope at, for example, 100x magnification, have an irregular surface, are prone to shape changes, and appear particularly non-spherical.

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

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

[0041] Preferably, the mannitol granules according to this disclosure exhibit almost no porosity at a magnification of, for example, 3000 times.

[0042] The term "microcrystalline" typically refers to a structure that, when observed under an electron microscope at, for example, 3000x magnification, has substantially microcrystals on its surface and very few larger crystals. According to this disclosure, microcrystals can be defined as crystals whose sum of length, width, and thickness is less than 25 μm. Microcrystals can have a wide variety of shapes, from round to elongated. The granules according to this disclosure preferably have a "non-fibrous" microstructure. In other words, the length-to-width ratio of microcrystals present on the surface of the granules according to this disclosure is preferably lower than the ratio observed for filaments. In fact, even if needle-like crystals may be present, they are present in very small quantities on the surface of the granules according to this disclosure. For comparison, U.S. Patent No. 6,998,481(B2) presents a photograph of granules having a so-called fibrous structure, in which only needle-like microcrystals are visible. Finally, the microcrystals of mannitol granules according to this disclosure are generally unoriented.

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

[0044] The mannitol granules according to this disclosure also differ from mannitol powder obtained by single-effect spray drying (without using a fluidized bed) of a mannitol solution, as their particles are composed of microcrystalline mannitol but have a very smooth surface, are spherical or "deformed sphere" in shape, and generally have a small diameter of 10–50 μm (see, e.g., Eva M. Littringer et al., "The morphology and various densities of spray dried mannitol," Powder Technology 246 (2013) 193–200, in particular Figure 1 p. 196). They are further distinguished from mannitol powder obtained by melt / extrusion, which consists of more compact and regular particles, are in the form of more or less angular blocks, and are composed of substantially oriented microcrystals.

[0045] Mannitol granules according to this disclosure can typically be obtained by a spray granulation process, and process mannitol granules are formed from a mannitol solution. Therefore, alternatively or additionally, microcrystalline mannitol granules according to this disclosure can be defined by the fact that they are granulated, obtained, or may be obtained by spray granulation, particularly by a fluidized bed spray granulation process. Alternatively or additionally, mannitol granules according to this disclosure can also be defined by the fact that they are not obtained by single-effect atomization, and / or by melt / extrusion, and / or by agglomeration of powders composed particularly of macrocrystalline particles, and / or by dry granulation.

[0046] The mannitol granules according to this disclosure are also characterized by the fact that mannitol contains at least 90% of the β-crystalline form. The crystalline polymorphism (crystalline form and percentage) of mannitol can be determined by those skilled in the art using infrared spectroscopy or X-ray powder diffraction, preferably X-ray powder diffraction. This can be done, for example, by carrying out the method disclosed in the Examples section below. Preferably, the mannitol granules according to this disclosure contain at least 95%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, and more preferably at least 100% of the β-crystalline form. It should be noted that these percentages of the β-crystalline form are typically expressed based on the sum of the α, β, and δ crystalline forms.

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

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

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

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

[0051] Preferably, the mannitol granules according to this disclosure have a volume D10 of 50 μm or more, preferably 60 μm or more, preferably 70 μm or more, and preferably 80 μm or more. Generally, they are 200 μm or less, or more preferably 150 μm or less, or more preferably 120 μm or less, or more preferably 110 μm or less, or more preferably 100 μm or less.

[0052] Preferably, the mannitol granules according to this disclosure have a volume D50 of 100 μm or more, preferably 120 μm or more, preferably 140 μm or more, and preferably 150 μm or more. Generally, it is 250 μm or less, or more preferably 200 μm or less, or more preferably 180 μm or less, or more preferably 170 μm or less.

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

[0054] Please note that the values ​​D10, D50, and D90 represent sizes where 10%, 50%, and 90% of the particles have a smaller particle size, respectively. The volume-based values ​​D10, D50, and D90 represent sizes where 10% by volume, 50% by volume, and 90% by volume have a smaller particle size, respectively.

[0055] The number or volume values ​​of D10, D50, and D90 can be determined by those skilled in the art, in particular, using a dry laser diffraction particle size analyzer, for example, according to the method disclosed in the Examples section below.

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

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

[0058] This aeration density and bulk density can be determined by a person skilled in the art using the method recommended by the European Pharmacopoeia, particularly in accordance with Method 1: "measurement in a graduated cylinder" described in European Pharmacopoeia 10.0, 2.9.34.

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

[0060] The mannitol granules according to the present invention may also be characterized by being mannitol for direct compression or "directly compressible" mannitol. The term "direct compression excipient" has also been used conventionally. Thus, the mannitol granules according to the present disclosure can be directly compressed, that is, they can be compressed without prior texturing or physical transformation treatments, such as pre-processing steps for dry or wet granulation. This is understood to mean that the mannitol granules can form tablets of sufficient hardness by direct compression only in the presence of an effective amount of lubricant. This "effective amount" is an amount that effectively enables the formation of tablets, i.e., typically, there is no adhesion or bonding, and the force of ejecting the tablets from the press is less than 1000 Newtons in the production of, for example, 10 tablets. This effective amount of lubricant generally does not exceed 3% by weight of the total weight of the powder being compressed. Bonding occurs when a portion of the material adheres to the die, and it is conceivable that this adhesion remains even after the tablets have been ejected. Bonding is visible on the tablet, where vertical lines exist, and corresponds to the locations where the product remains adhered to the die.

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

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

[0063] According to the test referred to as "Test A" in this disclosure, the tableting ability of the excipient under test is determined by preparing a convex 400 mg tablet having a diameter of 10 mm and a radius of curvature of 9 mm on a single-punch unfolding press that simulates compression on an industrial rotary press, and then measuring the hardness of the tablet.

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

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

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

[0067] Preferably, the mannitol granules according to this disclosure have a flow grade of 3 to 15 seconds, preferably 10 seconds or less, and preferably 8 seconds or less. Typically, it is 5 seconds or more, or even 6 seconds or more. This flow grade 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 "European Pharmacopoeia 7.0, 2.9.16, "Flow", with equipment for Figure 2.9.16.-2".

[0068] Preferably, the mannitol granules according to this disclosure are not easily fructile. This fructility can be determined by those skilled in the art according to the methods recommended by the European Pharmacopoeia, for example, according to the reference method described in European Pharmacopoeia 10.0,04 / 2012:20941 "2.9.41, Friability of Granules and Spheroids". For example, this can be done by carrying out the method disclosed in the Examples section below.

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

[0070] The mannitol granules according to this disclosure are mannitol, but these granules may contain small amounts of other components as long as they do not contradict the properties required in the present invention. Examples of other components include binders such as polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), cellulosic derivatives, acacia gum, gelatin, and starch derivatives (such as maltodextrin and tragacanth gum); minerals, sugars, and carbohydrates such as sugar alcohols other than mannitol; food additives, colorants, nutritional supplements, pharmaceuticals, veterinary or cosmetic active ingredients, preservatives, and stabilizers. Preferably, the content of other components in the granules, especially 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%, and even more preferably less than 0.5%, and these percentages are expressed as weight relative to the total weight of the granules.

[0071] In most preference, the mannitol granules according to this disclosure contain no other components. In the latter case, this means that the granules consist only of mannitol and residual impurities. In this regard, it should be noted that the mannitol according to this disclosure has an abundance of mannitol, particularly D-mannitol, preferably more than 95.0%, preferably more than 96.0%, preferably more than 97.0%, preferably more than 97.5%, preferably more than 98.0%, preferably more than 98.5%, and most preferably more than 99.0% by dry weight, with the remainder being residual impurities, typically resulting from the production of mannitol. The impurities typically include substances related to mannitol, particularly sorbitol, maltitol and isomalt, reducing sugars, nickel, and heavy metals. Their content can be determined by those skilled in the art, for example, according to methods recommended by the European Pharmacopoeia (e.g., the method described in reference "Mannitol, 01 / 2014:0559").

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

[0073] Fluidized air bed spray granulation process Another object of the present invention is a mannitol granulation process particularly useful for producing the mannitol granules disclosed above, which is a continuous process for granulation by spraying a mannitol solution onto a fluidized air bed. - The granulator fluidized bed temperature is 30°C or higher and 70°C or lower. - This is a mannitol granulation process characterized by the recycling of a portion of the mannitol.

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

[0075] This, too, is a continuous process. Traditionally, this means that the final product can be continuously recovered as long as the mannitol solution is supplied to the system.

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

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

[0078] The fluidized air flow rate is typically selected to have a linear velocity at the floor of 1.0 to 2.0 m / s, preferably about 1.5 m / s.

[0079] The fluidizing air temperature is typically set to control the fluidized bed temperature. For example, it may be between 100°C and 150°C. For example, it may be between 110°C and even 120°C. For example, it may be below 140°C. For example, it may be around 130°C.

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

[0081] Preferably, the mannitol solution to be sprayed contains 20% or more by weight of dry material, preferably 30% or more by weight, and preferably 35% or more by weight. Preferably, the concentration is 50% or less, preferably 45% or less, and preferably 40°C or lower. For example, it is selected in the range of about 38% to about 40%.

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

[0083] Preferably, spraying is performed using two-fluid spray nozzles. The number of these nozzles is usually appropriate to the size of the fluidized bed. These nozzles can be positioned either at the top ("top spray") or bottom ("bottom spray") of the fluidized bed.

[0084] Preferably, the solution supply rate is 1 m³ of fluidized bed. 2 The flow rate is 300 kg / h or more per unit area, and the fluidized bed is 1 m³. 2 The flow rate is 400 kg / h or less per unit area. Preferably, the fluidized bed is 1 m³. 2 A more than 310 kg / h per cubic meter of more efficient fluidized bed. 2 The flow rate is 320 kg / h or more per unit area. Preferably, a fluidized bed of 1 m³ 2 380 kg / h or less per unit, preferably 1 m³ of fluidized bed 2 350 kg / h or less per cubic meter, more preferably a fluidized bed of 1 m³ 2 The flow rate is 340 kg / h or less per unit area. For example, a 1 m³ fluidized bed. 2 This is equivalent to approximately 330 kg / h.

[0085] Preferably, the spray pressure is 1.0 bar or more and 4.0 bar or less. Preferably, it is 1.5 bar or more, preferably 2.0 bar or more, preferably 2.5 bar or more. Preferably, it is 3.5 bar or less, more preferably 3.0 bar or less.

[0086] Preferably, the spray air temperature is 20°C or higher and 100°C or lower. Preferably, it is 80°C or lower, preferably 60°C or lower, preferably 50°C or lower, preferably 40°C or lower, and preferably 30°C or lower. For example, it is equal to about 25°C.

[0087] Since this process is a continuous process that includes recycling, the mannitol granule fraction is continuously extracted from the granulator.

[0088] Preferably, particles having a size of 50 μm or larger, preferably 80 μm or larger, and more preferably about 100 μm or larger are extracted. It is understood that smaller particles will still be extracted unless the means used for this extraction (e.g., a classifier) ​​allows for a generally clean cut.

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

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

[0091] The process according to the present invention involves recycling granulated mannitol particles, particularly fine powder. The recycled fraction is reintroduced in a dry form; that is, the granulated mannitol particles are not redissolved in solution but are directly reintroduced into the granulator bed. The recycled particles typically originate from mannitol extracted from the granulator. They are recycled either as is or after grinding. Small amounts of fine particles transported with the effluent airflow can also be reintroduced into the recycling system, and these are generally in very small quantities compared to particles derived from mannitol extracted, for example, using a classifier.

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

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

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

[0095] Preferably, this separation is achieved by one or more sieves. Preferably, the cutoff threshold used for particles considered too fine is 50 μm or more and 150 μm or less. Preferably 80 μm or more, more preferably 90 μm or more. Preferably 130 μm or less, more preferably 110 μm or less. This cutoff threshold is, for example, about 100 μm. The passing fraction is typically and preferably introduced directly (without being ground) into the recycling system. Preferably, the cutoff threshold used for particles considered too coarse is 400 μm or more and 800 μm or less. Preferably 450 μm or more. Preferably 700 μm or less, preferably 600 μm or less, preferably 550 μm or less. This cutoff threshold is, for example, about 500 μm. The retained fraction is typically and preferably introduced into the recycling system after being ground.

[0096] Preferably, these sieving operations are performed sequentially. Preferably, the sieves are arranged to range from the highest cutoff to the lowest cutoff. Therefore, preferably, sieving to separate particles that are considered too coarse is performed before sieving to separate particles that are considered too fine.

[0097] The mannitol remaining after separating the particles that are considered too coarse from those that are considered too fine can be recovered and processed.

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

[0099] Preferably, the process includes an initial priming step to enable granulation to begin. For this step, powdered mannitol is introduced into the fluidized bed. Typically, half to all of the bed is filled with this mannitol powder. Preferably, the amount of mannitol is such that 1 m³ of the fluidized bed is filled with this mannitol powder. 2 The amount is less than 300 kg per unit. It should be noted that this "exogenous" mannitol represents a very small amount of mannitol compared to the total amount of mannitol used. For example, 200-600 kg of powder is used to produce 7 tons of mannitol granules over 24 hours. Typically, the amount of mannitol used for initial priming is preferably less than 10% of the weight of the mannitol granules produced and tends to approach 0% after several days of continuous production. In the following examples, crystallized mannitol powder (composed of mannitol macrocrystals) is used for initial priming. However, it is also possible to use textured mannitol, such as atomized or granulated mannitol.

[0100] If the mannitol granules according to the present invention contain other components besides mannitol, the granulation process according to the present disclosure includes the use of these other components, which can be introduced into the granulator chamber in a dry form, for example, via a recycling system or an additional inlet, and / or in the form of a suspension and / or solution, for example, via a sprayed mannitol solution. In a preferred embodiment, the granulation process is i1) Prepare a mannitol solution, i2) Spraying the mannitol solution into a fluidized bed granulator until mannitol particles are obtained, wherein the temperature of the fluidized bed is 30°C or higher and 70°C or lower. i3) Optionally, the mannitol particles from step i2) are cooled, preferably in a fluidized air bed. i4) Sieve away the mannitol particles from step i2) or step i3), Mannitol granules having a volume-average diameter D(4;3) of -90 μm or more and 400 μm or less, optionally, Mannitol particles (which may also be called "fine powder") having a diameter of less than -130 μm, preferably less than 110 μm, preferably less than 100 μm, and / or - To obtain mannitol particles (which may also be called "waste") having a diameter of more than 400 μm, preferably more than 450 μm, preferably more than 500 μm, i5) Recycle the fine powder from process i4) into the fluidized bed granulator in process i2), i6) includes crushing the waste from step i4) and recycling it into the granulator from step i2). Preferably, the mannitol granules in step i4) are in accordance with the mannitol granules of the present disclosure.

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

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

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

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

[0105] powder composition The present invention also relates to powdered compositions, particularly powdered compositions for direct compression, comprising mannitol granules according to the present disclosure and at least one other component. The present invention also relates to powdered compositions, particularly powdered compositions for direct compression, comprising mannitol granules obtained or obtainable according to a granulation process according to the present invention and at least one other component.

[0106] This powdered composition is preferred, Mannitol granules with a concentration of -30.0 to 99.9% as disclosed herein, - Consists of components other than mannitol granules as disclosed herein, ranging from -0.1% to 70.0%. The percentages are expressed in weight, and their sum equals 100%.

[0107] Other examples of components are typically as follows: - Direct compressible excipients or diluents other than mannitol according to the present invention, for example, (i) directly compressible sugar alcohols such as sorbitol, maltitol, xylitol, isomalt, lactitol, erythritol, or mannitol other than those according to the present invention in a directly compressible form; (ii) directly compressible sugars such as sucrose, dextrose, dextrate, lactose, allulose, etc. in a directly compressible form; (iii) microcrystalline cellulose; (iv) directly compressible minerals; - Lubricant; - Dispersants or disintegrants, such as sodium starch glycolate, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone (PVP), starch; - Granulating agents such as polyvinylpyrrolidone, cellulose derivatives, acacia gum, dextrose, gelatin, maltodextrin, starch, starch derivatives, and tragacanth gum; - Food additives, such as flavorings and acidifying agents; - Dyes such as inorganic dyes, pigments, or soluble dyes; - Flow agent (e.g., silicon dioxide), or anti-adhesion agent (e.g., talc); - Active ingredients, especially active ingredients in pharmaceuticals, veterinary medicines, nutritional supplements, or cosmetics.

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

[0109] Preferably, the powdered composition according to this disclosure has a content of 20% or less, preferably 30% or less, and preferably 40% or less of the mannitol granules according to the present invention, and this percentage is expressed as weight relative to the total weight of the powdered composition. The content of the mannitol granules is generally 99% or less, or more preferably 90% or less, or more preferably 80% or less, or more preferably 70% or less.

[0110] Generally, the disclosed powdered compositions have 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%, and preferably 1.0 to 2.0%, where these percentages are expressed by weight relative to the total weight of the powdered composition.

[0111] In advantageous embodiments, particularly in the case of compositions for the manufacture of orally disintegrating tablets, the disclosed powdered composition comprises a disintegrant, preferably a superdisintegrant.

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

[0113] These may be compositions designed for molding by wet or dry granulation, such as dry granulation by slugging or roller compression.

[0114] Tablet preparation The present invention also relates to a process for preparing tablets, which preferably involves using a rotary press to directly compress the powdered composition according to the present disclosure.

[0115] tablet The subject of the present invention is also a powdered composition according to the present invention, or a tablet obtained by a process for preparing tablets by direct compression according to the present invention.

[0116] Conventionally, in this disclosure, “tablet” is intended to mean a solid preparation obtained by direct compression of a powdered composition. Tablets may be for, for example, food, pharmaceutical, cosmetic, or dietary supplement applications. They may be tablets to be licked, chewed, or swallowed, orally disintegrating tablets, or effervescent tablets. These tablets may be for human, adult, or pediatric, or animal use. They may also be tablets for chemical or agrochemical applications. These tablets may be single-layer or multi-layer tablets. In this disclosure, tablets preferably have a curved shape, in other words, a convex shape.

[0117] Preferably, the tablets according to the present invention have a hardness of 50 N or more, preferably 75 N or more, preferably 100 N or more, preferably 150 N or more, preferably 200 N or more, preferably 210 N or more, preferably 220 N or more, preferably 230 N or more, or even 240 N or more, or even 250 N or more, or even 300 N or even 350 N or more. Generally, this hardness is 450 N or less, or even 400 N or less.

[0118] In an advantageous embodiment, the tablets are intended for use in individuals with difficulty swallowing, and / or for use in children and / or the elderly, and / or for use in individuals suffering from dysphagia.

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

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

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

[0122] In this disclosure, the amounts of components are generally expressed as weight percentages. Unless otherwise specified, these weights are the raw amounts of the components in powder or oil form. These powder components generally contain small amounts of water (also called % water or "mass loss due to dehydration") and some impurities.

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

[0124] The present invention will be better understood with the help of the following embodiments, which are intended to be illustrative and non-limiting. [Examples]

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

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

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

[0128] [Table 1]

[0129] The mannitol granules obtained in this manner were characterized after 48 hours of continuous operation and compared with commercially available and / or conventional mannitol.

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

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

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

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

[0134] 5. Determination of flow grade. The flow grade 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; apparatus according to Figure 2.9.16.-2).

[0135] The results obtained are shown in the table in Figure 2, and in Figures 3 (microscopic examination) and 4 (severity-of-grain size distribution).

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

[0137] 6. Electrostatic Charge. Electrostatic charge was measured using GRANUCHARGE®. The GRANUCHARGE® instrument automatically and accurately measures the amount of electrostatic charge generated within a powder as it flows in contact with a selected material. The powder sample flows inside a vibrating V-tube and falls into a Faraday cup connected to a potentiometer. The potentiometer measures the charge acquired by the powder as it flows through the V-tube. For each experiment conducted using GranuCharge, the following method was used: The free-flow characteristics of the powder allowed for simple rotation of the beaker to supply it to the stainless steel tube circuit. The amount of powder used for measurement could vary between 20 and 50 g. Recycling after measurement was not possible. Three different [temperature / humidity] pairs were selected to evaluate their effect on the obtained electrostatic charge. To avoid temperature dependence, the inventors used absolute humidity as the reference value (water (g) divided by the amount of dry air (kg)).

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

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

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

[0141] 7. Friability. Friability was measured using a Friabimat SA-400 (COPLEY) according to the method adopted from European Pharmacopoeia 10.0, 2.9.41 "Friability of Granules and Spheroids". Triple tests were performed (10 g sample per test). The operating conditions were as follows: 400 vibrations / min for 240 seconds. The volume particle size distribution of the powder before and after passing through the Friability Tester was measured according to the method described in item 4. Two measurements were performed per sample. No air pressure was applied to avoid fracture. The particle size curves before and after passing through the Friability Tester could be superimposed. In other words, granules according to this disclosure are not easily broken.

[0142] 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 bar. 250 mL tall beaker. The dissolution time obtained for MG4 mannitol granules was 30 seconds.

[0143] C. Direct Compression Test MG1, MG2, and MG3 mannitol granules were initially tested for their compression behavior on a KORSCH XP1 single-punch press. Extreme compression conditions were selected to test the resistance of the mannitol granules to stacking (convex tablets, compression rate of 60 tablets per minute).

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

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

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

[0147] The results are shown in Figure 5.

[0148] Despite extreme compression conditions, no lamination was observed. Hardnesses exceeding 300N, and even higher hardnesses exceeding 350N, were achieved. It is also noteworthy that the three batches exhibited similar compression behavior: the process according to the present invention is robust, reproducible, and produces equivalent powder from one batch to the next.

[0149] Next, the mannitol granules were tested for their compression behavior using a single-punch unfolding press that simulates compression in an industrial rotary press, and compared to commercially available and / or prior art mannitol powders.

[0150] Except for the press used, the tablets were prepared using the same method as in the previous test.

[0151] The press used was a single-punch unfolding press that simulated compression on an industrial rotary press (STYLCAM® 200R, MEDEL'PHARM) controlled by ANALIS software using the STYLCAM® standard profile. This press advantageously allows for the simulation of the operation of an industrial rotary press. Two series of tests were conducted. In the first test, the press was set to a speed of 25 tablets / minute. In the second test, the press was set to a speed of 40 tablets / minute. This latter speed corresponds to an industrial production rate of 250,000 tablets per hour.

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

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

[0154] At the two speeds tested, the mannitol granules according to this disclosure did not stack, while PARTECK® M200 and PEARLITOL® 200 SD stacked after 10–11 kN. Therefore, the highest hardness up to approximately 250 N (at 16 kN Fc) can be achieved using mannitol granules as disclosed.

[0155] Complementary compression tests were performed on tablets containing the active pharmaceutical ingredient (results not shown herein), and the same trend was observed: namely, the mannitol granules according to this disclosure did not stack.

[0156] In this way, the disclosed mannitol granules enable the production of high-hardness tablets at high production rates suitable for industrial tablet production. Their resistance to stacking allows for an increase in the amount of incompressible component (typically the active ingredient) in the tablet and / or a reduction in tablet size. This is particularly advantageous for improving treatment compliance in people with swallowing difficulties, such as children, the elderly, and / or individuals with dysphagia.

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

[0158] The mannitol granules according to this disclosure possess the qualities necessary for compression excipients intended for the industrial production of tablets. They enable accurate die filling, i.e., uniform and reproducible filling with precise amounts of powder, and flow accurately in equipment used in direct compression. They are chemically and physically stable. They have sufficient cohesiveness to allow them to be transported or to be used in the preparation of mixtures. They do not interfere with the bioavailability of other components of the powder and enable the production of tablets that dissolve well in contact with water in particular. They enable uniform mixing of the components of the composition and have good absorption capacity. They enable the formulation of tablets that have the acceptable texture and taste required when the tablets are intended to be ingested. They do not incur packaging and transport costs in accordance with commercial standards, i.e., there is a good ratio between the weight of the powder to be transported and the volume required to package that weight.

[0159] Next, the mannitol granules according to this disclosure were used in the preparation of orally disintegrating tablets.

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

[0161] When the powder was pressed to produce chamfered tablets with a diameter of 10 mm (see BEVEL EDGE D10 upper and lower punches 2010060-5-1, die 2010060-1), the weight was approximately 380 mg and the hardness was approximately 75 N. A 10% pre-compression was applied.

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

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

[0164] The in vivo disintegration time of tablets was evaluated using the method described in European Pharmacopoeia 7.1,04 / 2011:20901, "2.9.1. Disaggregation of tablets and capsules".

[0165] Without applying pre-compression force, the dissolution time was 30 seconds in vivo and 10 seconds in vitro. With a pre-compression force of 1.45 kN applied, the dissolution time was 35 seconds in vivo and 10 seconds in vitro. These dissolution times are excellent for orally disintegrating tablets.

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

[0167] D. Use of the granules in other applications as disclosed herein The mannitol granules according to this disclosure have lower electrostatic charge, better flowability, and are less prone to breakage (Section B) than those obtained using PEARLITOL® 200SD, making them excellent candidates for use as container fillers for capsules, sachets, and logs, or for use in continuous processes requiring continuous powder mixing and administration steps. In addition, the mannitol granules according to this disclosure have a pleasant, slightly sweet taste and a good solubility profile. These qualities are particularly desirable for use in sachets or logs where the ingested powder comes into direct contact with the oral cavity. The mannitol granules according to this disclosure are also suitable for use in wet or dry granulation.

[0168] To confirm the potential of the granules according to the present invention for these applications, the following tests were conducted.

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

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

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

[0172] The obtained granulated product was measured for particle size (by the method described in Section B.4), packing density, air permeability density, and moisture content.

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

[0174] 3. Use in dry granulation Next, mannitol granules were tested for use in dry granulation ("slugging"). The granulated powder composition was as follows: 15% by weight propanolol (active ingredient), 54% by weight mannitol granules, 30% by weight microcrystalline cellulose (MICROCEL® 102SD, ROQUETTE), and 1% by weight magnesium stearate. The composition was prepared as follows: After passing through a 710 μm sieve, the propanolol, mannitol granules, and microcrystalline cellulose were mixed at 40 rpm for 10 minutes (T2F, TURBULA), then passed through a 355 μm sieve, magnesium stearate was added, and the mixture was mixed at 40 rpm for 1 minute. Next, the powder composition was compressed using the following parameters. STYL'One Evolution press (MEDELPHARM), punch and die: circular, chamfered EU-B, 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 obtained tablets was measured using a durometer (ST50, SOTAX) and was approximately 115 N. The obtained tablets were crushed. The dry crushing parameters were as follows: calibration grid 1016 μm, mesh type: file, rotor type: square, rotation speed 3000 rpm.

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

Claims

1. Microcrystalline mannitol granules, - The mannitol has a β-crystal content of 95% or more, - The microcrystalline mannitol granules have a volume average diameter D(4;3) of 90 μm or more and 250 μm or less. - The microcrystalline mannitol granules have an air permeability density of 600 g / L or more and 750 g / L or less. - The microcrystalline mannitol granules are 0.50 m ２ Having a specific surface area of ​​3.00 m² / g or more, The microcrystalline mannitol granules have a packing density of 700 g / L or more and 850 g / L or less. - Microcrystalline mannitol granules characterized in that, if the microcrystalline mannitol granules contain other components, the content of the other components is less than 10.0%, and this percentage is expressed as a weight ratio to the total amount of the microcrystalline mannitol granules.

2. The microcrystalline mannitol granules according to claim 1, characterized by having an air permeability density of 610 g / L or more.

3. 0.60m ２ The microcrystalline mannitol granules according to claim 1, characterized by having a specific surface area greater than / g.

4. A powdered composition comprising microcrystalline mannitol granules as described in claim 1 and at least one other component.

5. A process for preparing tablets, comprising direct compression of the powdered composition according to claim 4.

6. A tablet comprising the powdered composition described in claim 4.

7. Use of the microcrystalline mannitol granules described in claim 1 as a direct compression excipient.

8. Use of the microcrystalline mannitol granules according to claim 1 as a filler for filling at least one of a capsule, sachet, or log.

9. Use of the microcrystalline mannitol granules described in Claim 1 as a filler in powder molding.

10. A process for producing microcrystalline mannitol granules according to Claim 1, comprising a continuous process for granulation by fluidized air bed spraying of a mannitol solution, - The granulator fluidized bed temperature is 30°C or higher and 70°C or lower. - A process for granulating mannitol, characterized in that a portion of the mannitol is recycled.

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

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

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

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

15. A process for granulating mannitol according to any one of claims 10 to 12, characterized in that the mannitol solution to be sprayed contains 20% or more by weight and 50% or less by weight of dry material.

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